ArticlePDF AvailableLiterature Review

Ketamine for depression

International Review of Psychiatry

February 2021
33(10):1-32

DOI:10.1080/09540261.2020.1854194

Authors:

Luke A Jelen

King's College London

James M Stone

Brighton and Sussex Medical School

Over the last two decades, the dissociative anaesthetic agent ketamine, an uncompetitive N-Methyl-D-Aspartate (NMDA) receptor antagonist, has emerged as a novel therapy for treatment-resistant depression (TRD), demonstrating rapid and robust antidepressant effects within hours of administration. Ketamine is a racemic mixture composed of equal amounts of (S)-ketamine and (R)-ketamine. Although ketamine currently remains an off-label treatment for TRD, an (S)-ketamine nasal spray has been approved for use in TRD (in conjunction with an oral antidepressant) in the United States and Europe. Despite the promise of ketamine, key challenges including how to maintain response, concerns regarding short and long-term side-effects and the potential for abuse remain. This review provides an overview of the history of ketamine, its use in psychiatry and its basic pharmacology. The clinical evidence for the use of ketamine in depression and potential adverse effects associated with treatment are summarized. A synopsis of some of the putative neurobiological mechanisms underlying ketamine's rapid-acting antidepressant effects is provided before finally outlining future research directions, including the need to identify biomarkers for predicting response and treatment targets that may be used in the development of next-generation rapid-acting antidepressants that may lack ketamine's side-effects or abuse potential.

Summary of placebo-controlled studies that have assessed the antidepressant effects of ketamine ((R,S)-ketamine) and (S)-ketamine.

…

Figures - uploaded by Luke A Jelen

Content may be subject to copyright.

Content uploaded by Luke A Jelen

Content may be subject to copyright.

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=iirp20

International Review of Psychiatry

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iirp20

Ketamine for depression

Luke A. Jelen & James M. Stone

To cite this article: Luke A. Jelen & James M. Stone (2021): Ketamine for depression,

International Review of Psychiatry

To link to this article: https://doi.org/10.1080/09540261.2020.1854194

Published online: 11 Feb 2021.

Submit your article to this journal

View related articles

View Crossmark data

REVIEW ARTICLE

Ketamine for depression

Luke A. Jelen

a,b

and James M. Stone

a,b

Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s

College London, London, United Kingdom;

South London and Maudsley NHS Foundation Trust, London, United Kingdom

ABSTRACT

Over the last two decades, the dissociative anaesthetic agent ketamine, an uncompetitive N-

Methyl-D-Aspartate (NMDA) receptor antagonist, has emerged as a novel therapy for treatment-

resistant depression (TRD), demonstrating rapid and robust antidepressant effects within hours

of administration. Ketamine is a racemic mixture composed of equal amounts of (S)-ketamine

and (R)-ketamine. Although ketamine currently remains an off-label treatment for TRD, an (S)-

ketamine nasal spray has been approved for use in TRD (in conjunction with an oral antidepres-

sant) in the United States and Europe. Despite the promise of ketamine, key challenges includ-

ing how to maintain response, concerns regarding short and long-term side-effects and the

potential for abuse remain. This review provides an overview of the history of ketamine, its use

in psychiatry and its basic pharmacology. The clinical evidence for the use of ketamine in

depression and potential adverse effects associated with treatment are summarized. A synopsis

of some of the putative neurobiological mechanisms underlying ketamine’s rapid-acting anti-

depressant effects is provided before finally outlining future research directions, including the

need to identify biomarkers for predicting response and treatment targets that may be used in

the development of next-generation rapid-acting antidepressants that may lack ketamine’sside-

effects or abuse potential.

ARTICLE HISTORY

Received 15 July 2020

Accepted 18 November 2020

KEYWORDS

Ketamine; (S)-ketamine;

antidepressant; depression;

mechanism of action

Introduction

Depression remains a leading cause of disability world-

wide (WHO, 2017). It is a major contributor to the glo-

bal burden of disease, associated with high rates of

carer burden and rising socioeconomic and healthcare

costs. There are two main limitations to current treat-

ment strategies for depression, which predominantly

focus on targeting deficits in monoaminergic neuro-

transmission. Firstly, there is a significant delay in the

onset of therapeutic action (from weeks to months) and

secondly, up to a third of patients fail to demonstrate

an adequate response, with many developing persistent,

treatment-resistant depression (TRD) (Al-Harbi, 2012).

At the turn of the millennium, there had been no

new breakthrough pharmacological treatments for

depression since the introduction of selective serotonin

reuptake inhibitors (SSRIs) in the late 1980s. This

changed with the discovery that ketamine, an uncom-

petitive N-Methyl-D-Aspartate (NMDA) glutamate

receptor antagonist, could produce rapid and profound

reductions in depressive symptoms following a single

subanaesthetic infusion in individuals with major

depressive disorder (MDD) (Berman et al., 2000). This

finding has now been replicated and confirmed in sev-

eral clinical trials in both unipolar and bipolar depres-

sion (including treatment-resistant individuals),

resulting in a paradigm shift for depression research

and treatment (Krystal et al., 2019).

Despite cautious optimism surrounding the poten-

tial of ketamine for depression, a number of uncertain-

ties remain. These include understanding its underlying

therapeutic mechanism of action, how best to maintain

response, and concerns regarding potential short and

long-term side-effects, including abuse potential. In this

review, we give a brief historical overview of the use of

ketamine in psychiatry before addressing a number of

key questions to provide the reader with an update on

the current status of the use of ketamine for depression,

before outlining areas for future consideration.

What is the history of ketamine use

in psychiatry?

Ketamine, originally designated as CI-581, was first

synthesized in 1962 by Calvin Stevens at the Parke

CONTACT Luke A. Jelen luke.jelen@kcl.ac.uk Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry,

Psychology and Neuroscience, King’s College London, PO72 De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom

ß2020 Institute of Psychiatry and Johns Hopkins University

INTERNATIONAL REVIEW OF PSYCHIATRY

https://doi.org/10.1080/09540261.2020.1854194

Davis Lab. It is a structural analogue of its parent

compound phencyclidine and was initially developed

with the aim of finding an agent with similar anaes-

thetic properties but that was shorter acting and

lacked the prolonged emergence delirium associated

with phencyclidine (Domino, 1980). In the first clin-

ical study of ketamine, it was found to be a powerful

anaesthetic and analgesic, producing a unique state of

altered consciousness (Corssen & Domino, 1966).

Subjects reported feeling as though they were ‘in

outer space’,or‘had no arms or legs’, and the term

‘dissociative anaesthetic’, which is still in use today,

was first coined (Domino, 2010). Following approval

by the US Food and Drug Administration (FDA) in

1970, ketamine was used as a battlefield anaesthetic in

the Vietnam War due to its fast onset and recovery

period, ability to maintain or elevate blood pressure

in trauma situations and its minimal effects on the

respiratory drive. Because of these qualities, it is still

frequently used as an anaesthetic in situations where

airway management is difficult or impossible (Kurdi

et al., 2014).

As ketamine was being studied as an anaesthetic

agent, its potential application to treat psychiatric and

psychological conditions was also being considered.

In Iran, ketamine as an adjunct to psychotherapy at

subanaesthetic doses (0.4–0.6 mg/kg) was reported to

be an effective abreactive agent in a number of condi-

tions including depression, anxiety, obsessive-compul-

sive neurosis, conversion reaction and

hypochondriasis with the authors highlighting the

importance of the drugs, ‘mind expanding effects’

(Khorramzadeh & Lotfy, 1973). At the same time in

Argentina, ketamine was being examined as an

adjunct for antidepressive psychotherapy to facilitate

regression (Fontana, 1974), while in Mexico, others

were exploring the use of ketamine in group settings

as part of psychedelic psychotherapy sessions in

patients with neurosis and personality disorders (Kolp

et al., 2007). From 1985, Krupitsky utilized ketamine-

assisted psychedelic therapy in a range of neurotic

and personality disorders with particularly impressive

results in the treatment of alcoholism (Krupitsky &

Grinenko, 1997). Total abstinence for more than one

year was observed in 65.8% (73 out of 111) alcoholic

patients in the ketamine psychedelic therapy group,

compared to 24% (24 out of 100) patients in the con-

ventional treatment control group (p<0.01).

Following this exploratory work, it was in 2000

that the findings from the first randomized controlled

trial (RCT) of ketamine in depression were reported

(Berman et al., 2000). In this landmark study, Berman

and colleagues used a subanaesthetic dose of intraven-

ous (IV) ketamine (0.5 mg/kg infused over 40 min) in

a randomized, crossover, double-blind design in eight

medication-free patients with major depressive dis-

order (MDD) and one patient with bipolar disorder.

Ketamine produced a significant antidepressant effect

as soon as 4 h after the infusion that increased pro-

gressively up to 72 h (mean Hamilton Depression

Rating Scale scores decreased by 14 ± SD 10 points vs.

0 ± 12 points, after ketamine and placebo treatment

respectively) (Berman et al., 2000).

What is the basic pharmacology of ketamine?

Ketamine is a chiral arylcyclohexalamine and is classi-

fied as an uncompetitive NMDA receptor antagonist.

However, ketamine has a complex pharmacological

profile and also interacts with a range of other recep-

tors and systems including c-amynobutyric acid

(GABA), dopamine, serotonin, opioid, and cholinergic

receptors. With a few exceptions, including interac-

tions with the dopamine receptor D

and nicotinic

acetylcholine receptors by ketamine metabolites, the

affinity for these other receptors is far weaker than

the antagonism of the NMDA receptor. For an exten-

sive review and summary of receptor binding studies

see Zanos et al. (2018).

Ketamine refers to (R,S)-ketamine, a racemic mix-

ture composed of two enantiomers, (S)- and (R)-keta-

mine (esketamine and arketamine respectively).

Although most commercially available pharmaco-

logical preparations are made up of an equimolar

mixture of the two, the separate enantiomers have

also been investigated individually to varying degrees.

(S)-ketamine binds to the NMDA receptor with three

to four times the affinity compared with (R)-ketamine

(Ebert et al., 1997) and is a more potent anaesthetic

and analgesic (White et al., 1980,1985). While both

(S)-ketamine and (R)-ketamine appear to have rapid

antidepressant effects (Muller et al., 2016), there has

been limited clinical work investigating (R)-ketamine.

However, accumulating preclinical evidence suggests

(R)-ketamine may have more potent and longer-last-

ing antidepressant effects than both (R,S)-ketamine

and (S)-ketamine, with fewer side effects (Hashimoto,

2020; Jelen et al., 2020)

Ketamine is metabolized in the body to norket-

amine, hydroxynorketamines, hydroxyketamine and

dehyronorketamine (Zarate, Brutsche, Laje, et al.,

2012). In preclinical work, 2R,6R-hydroxynorketamine

(2R,6R-HNK) has been reported to have antidepres-

sant-like effects without ketamine-related behavioural

2 L. A. JELEN AND J. M. STONE

side-effects (motor incoordination, pre-pulse inhib-

ition deficits, ketamine-related discrimination

responses or increased drug self-administration)

(Fukumoto et al., 2019; Pham et al., 2018; Zanos

et al., 2016), although the literature remains divided

(Shirayama & Hashimoto, 2018; Yamaguchi et al.,

2018; Yang et al., 2017). The (S)- metabolite (S)-nor-

ketamine has also been shown to have antidepressant-

like effects that are similarly potent to its parent

compound but with fewer associated side-effects

(Yang, Kobayashi, et al., 2018).

Several different routes of ketamine administration

have been used in depression, including intravenous

(IV), intramuscular, intranasal, sublingual, and oral

routes each with their own advantages and challenges.

IV administration provides the most reliable dosing

with 100% bioavailability. For alternative routes

approximate bioavailability values are as follows;

intramuscular (93%), intranasal (45%), sublingual

(30%) and oral (20%) (Peltoniemi et al., 2016; Zanos

et al., 2018).

What is the evidence for the use of

intravenous ketamine in depression?

In the two decades since the pivotal study from

Berman and colleagues, the evidence base surround-

ing the use of ketamine in unipolar and bipolar

depression has been growing (Table 1). An initial rep-

lication study was published six years later in a group

of 18 patients with treatment-resistant MDD using an

identical study design (Zarate et al., 2006). Here, simi-

lar results were reported with significant antidepres-

sant effects emerging after 110 min after the infusion,

which peaked after 1 day, before fading after 1 week

(Zarate et al., 2006). The most common side-effect

was acute dissociative symptoms, however in general

these resolved within 80 min after the infusion. This

group subsequently performed two further similar

studies in patients with bipolar I or II depression who

were maintained on lithium or valproate

(Diazgranados et al., 2010; Zarate, Brutsche, Ibrahim,

et al., 2012). In the first study, depressive symptoms

significantly improved within 40 min and remained

significant through day 3, with a response rate of 71%

following ketamine compared to 6% for placebo

(Diazgranados et al., 2010). In the second study, rapid

and robust antidepressant effects were again seen

within 40 min, remaining significant up to 3 days after

the infusion, with response rates of 79% and 0% for

ketamine and placebo, respectively (Zarate, Brutsche,

Ibrahim, et al., 2012).

One of the limitations of these studies is the diffi-

culty in maintaining the blind as ketamine produces

clear dissociative symptoms. Other researchers have

used midazolam, a benzodiazepine, as an active pla-

cebo, in an attempt to maintain the blind while using

ketamine (Fava et al., 2020; Murrough et al., 2013;

Murrough, Soleimani, et al., 2015). In a large study of

73 patients with treatment-resistant MDD, it was

demonstrated that IV ketamine treatment resulted in

a significantly greater improvement in the MADRS

score 24 h after ketamine administration than the

midazolam treated group, with response rates of 64%

and 28% respectively (Murrough et al., 2013). In

another large multi-site parallel design dose-ranging

trial, comparing IV ketamine doses of 0.1 mg/kg,

0.2 mg/kg, 0.5 mg/kg and 1.0 mg/kg with midazolam

0.045 mg/kg, only the standard dose (0.5 mg/kg) and

high dose (1.0 mg/kg) were superior to the active pla-

cebo (Fava et al., 2020).

While many ketamine studies were carried out in

medication-free MDD patients, other trials have

examined adjunctive ketamine treatment in individu-

als also taking oral antidepressants. In a study of 27

individuals with MDD, maintained on their usual

antidepressant medication, IV ketamine treatment

was superior to placebo from days 1 through to day 7

(10/27 patients responded to ketamine, only 1/19

responded to placebo) (Sos et al., 2013). A further

study examined single IV ketamine versus placebo

augmentation to newly initiated escitalopram in 30

subjects with MDD (Hu et al., 2016). At the 4-week

endpoint, there was a significantly greater response in

the ketamine þescitalopram group than the place-

bo þescitalopram group (92.3% and 57.1% respect-

ively) with a significantly shorter time to response

and remission.

Findings from studies examining the effect of a

single dose of IV ketamine infusion in depression

have also been summarised in meta-analyses. One

meta-analysis examined nine studies (n¼234) in

patients with MDD and bipolar depression and

demonstrated that ketamine reduced depression sig-

nificantly more than placebo/active placebo begin-

ning at 40 min, peaking at day 1 (Hedges’g¼

1.00, 95%CI, 1.28 to 0.73, p<0.001), and los-

ing superiority by days 10–12 (Kishimoto et al.,

2016). A further meta-analysis examined the effects

of a single dose of ketamine on depressed patients

who had suicidal ideation at baseline and demon-

strated that ketamine rapidly (within 1 day) reduced

suicidal ideation significantly on both clinician-

administered and self-report outcome measures,

INTERNATIONAL REVIEW OF PSYCHIATRY 3

Table 1. Summary of placebo-controlled studies that have assessed the antidepressant effects of ketamine ((R,S)-ketamine) and (S)-ketamine.

Study Design Patient group nDosing regime Outcome Antidepressant effects

Single administration

(Berman et al., 2000) Randomized, placebo-controlled,

double-blind crossover study

MDD and BD 7 IV ketamine infusion

(0.5 mg/kg over 40 min)

HAM-D Reductions in the HAM-D of

14 ± 10 vs. 0± 12, for ketamine

and placebo, respectively

(Zarate et al., 2006) Randomized, placebo-controlled,

double-blind crossover study

TRD (MDD)

HAM-D 18

18 IV ketamine infusion

(0.5 mg/kg over 40 min)

HAM-D-21 Very large effect size for

ketamine at 24 h post-infusion, d

¼1.46

71% response rate at 24 h, 35%

response at 1 week

(Diazgranados et al., 2010) Randomized, placebo-controlled,

double-blind, crossover, add-on

study (to lithium or valproate)

TRD (BD)

MADRS 20

18 IV ketamine infusion

(0.5 mg/kg over 40 min)

MADRS Responses to ketamine and

placebo were 71% and 6%,

respectively

Effect size of ketamine largest at

day 2, d ¼0.8

(Zarate, Brutsche,

Ibrahim, et al., 2012)

Randomized, placebo-controlled,

double-blind crossover study, add

on study (to lithium or valproate)

TRD (BD)

MADRS 20

15 IV ketamine infusion

(0.5 mg/kg over 40 min)

MADRS The response rate of 79% to

ketamine vs. 0% for placebo

(Murrough et al., 2013) Two-site, parallel-arm, randomized

controlled trial of a single infusion

of ketamine compared to an

active placebo control, midazolam

TRD (MDD)

IDS-C 32

73 IV ketamine infusion

(0.5 mg/kg over 40 min)

MADRS MADRS scores at 24 h post-

infusion were 7.95 [95%CI,

3.21–12.71] lower in the

ketamine vs. the

midazolam group

Response rates of 64% for

ketamine vs. 28% for midazolam

Large effect size of ketamine,

NNT ¼2.8

(Sos et al., 2013) Randomized, placebo-controlled,

double-blind crossover study in

addition to usual

antidepressant medication.

MDD

MADRS 20

27 IV ketamine infusion

(0.54 mg/kg within 30 min)

MADRS Ketamine was superior to

placebo in all visits (day 1, 4,

and 7)

Effect size of ketamine largest at

day 1, d ¼0.62

(Lapidus et al., 2014) Randomized, placebo-controlled,

double-blind crossover study, add

on study (to stable dose of

antidepressant)

TRD (MDD) 20 Intranasal ketamine 50mg

(5 10 mg over 20 min)

MADRS MADRS scores at 24 h post-

infusion were 7.6 ± 3.7 [95%CI,

3.9–11.3] lower in the ketamine

vs. placebo group

Response rate of 44% to

ketamine vs. 6% following

placebo at 24 h

(Murrough, Soleimani,

et al., 2015)

Randomized, placebo-controlled,

double-blind crossover trial of a

single infusion of ketamine

compared to an active placebo

control, midazolam

MDD, BD, PTSD

4 on suicide

item of MADRS

24 IV ketamine infusion

(0.5 mg/kg over 40 min)

BSI BSI score was not different

between the treatment groups at

24 h (p¼0.32). However, there

was a significant difference at

48 h (p¼0.047)

(Downey et al., 2016) Two site, parallel-arm, randomized,

double-blind, controlled study of a

single infusion of ketamine

compared to lanicemine

MDD 60 IV ketamine infusion

(0.5 mg/kg over 60 min)

MADRS Neither drug improved mood

rating scale scores more than

saline infusion

(Hu et al., 2016) Parallel arm, randomized controlled

trial of a single infusion of

ketamine and escitalopram 10 mg/

MDD

(55.6% TRD)

HAM-D 24

30 IV ketamine infusion

(0. 5 mg/kg over 40 min)

MADRS At 4 weeks greater response in

ketamine þescitalopram vs

(continued)

4 L. A. JELEN AND J. M. STONE

Table 1. Continued.

Study Design Patient group nDosing regime Outcome Antidepressant effects

day compared to placebo and

escitalopram 10 mg/day

placebo þescitalopram (92.3% v.

57.1%, p¼0.04)

(Singh, Fedgchin, Daly,

Xi, et al., 2016)

Parallel arm, randomized placebo-

controlled, double-blind study

TRD (MDD)

IDS-C 34

30 IV (S)-ketamine infusion

0.2 mg/kg or 0.4 mg/kg

MADRS The reduction in MADRS total

score 24 h after treatment, was

significantly greater in both (S)-

ketamine groups compared with

the placebo group. Reductions in

MADRS score of 16.8 for

0.2 mg/kg, 16.9 for 0.4 mg/kg

and 3.8 for placebo.

(Su et al., 2017) Parallel arm, randomized placebo-

controlled, double-blind study

TRD (MDD)

HAM-D 18

71 IV ketamine infusion

(0.2 mg/kg or 0.5 mg/kg

over 40 min)

HAM-D-17 Significant dose-related ketamine

effect on HAM-D scores.

The responder analysis also

revealed a significant dose-

related effect (saline: 12.5%,

0.2 mg/kg: 39.1% 0.5 mg/

kg: 45.8%)

(Cao et al., 2018) Parallel arm, randomized placebo-

controlled, double-blind study

TRD (MDD)

HAM-D 18

55 IV ketamine infusion

(0.2 mg/kg or 0.5 mg/kg

over 40 min)

HAM-D-17 At 2h post-treatment 11/18

(61%) infused with 0.5 mg/kg

showed significant response, 5/

19 (26%) in the 0.2 mg/kg group

and only 2/18 (11%) in the

saline group

(Chen et al., 2018) Parallel arm, randomized placebo-

controlled, double-blind study

TRD (MDD) 24 IV ketamine infusion

(0.2 mg/kg or 0.5 mg/kg

over 40 min)

HAM-D-17 Significant treatment response

after 0.5 mg/kg ketamine infusion

at 240 min (37.5% vs. 0% vs. 0%,

2 (df) ¼6.86 (2), p¼0.032),

and 1 day later (50% vs. 12.5%

vs. 0%, 2 (df) ¼6.57 (2),

p¼0.037) compared with

0.2 mg/kg ketamine and normal

saline control groups

(Fava et al., 2020) Six site, parallel arm, randomized

placebo-controlled, double-blind

study of four different doses of

ketamine compared to active

placebo control, midazolam

TRD (MDD)

MADRS 20

99 IV ketamine infusion

(0.1 mg/kg, 0.2 mg/kg,

0.5 mg/kg or 1.0 mg/kg

over 40 min)

HAM-D-6 Overall group time interaction

effect was significant for the

primary outcome measure, the

HAM-D-6

Pairwise comparisons controlling

for multiple comparisons,

standard dose (0.5 mg/kg) and

high dose (1 mg/kg) of

intravenous ketamine were

superior to active placebo

(Grunebaum et al., 2018) Parallel arm, randomized placebo-

controlled, double-blind study

MDD with

suicidal ideation

HAM-D 17

80 IV ketamine infusion

(0.5 mg/kg over 40 min)

SSI Reduction in SSI score at day 1

was 4.96 points greater for the

ketamine group compared with

the midazolam group (95%CI,

2.33–7.59; Cohen’sd¼0.75).

Proportion of responders at day

1 was 55% for the ketamine

(continued)

INTERNATIONAL REVIEW OF PSYCHIATRY 5

Table 1. Continued.

Study Design Patient group nDosing regime Outcome Antidepressant effects

group and 30% for the

midazolam group. NNT ¼4.0

(Nugent et al., 2019) Randomized, placebo-controlled,

double-blind crossover study

TRD (MDD)

MADRS 20

35 IV ketamine infusion

(0.5 mg/kg over 40 min)

MADRS MADRS scores were significantly

lower post-ketamine infusion

compared to placebo (F

¼84.5, p<0.001)

Repeated administration

(Singh, Fedgchin, Daly,

De Boer, et al., 2016)

Fourteen site, parallel arm,

randomized placebo-controlled,

double-blind study

TRD (MDD) 67 IV ketamine infusion

(0.5 mg/kg over 40 min) 2

or 3 times a week

over 4 weeks

MADRS In the twice-weekly dosing

groups, the mean change in

MADRS score at day 15 was

18.4 (SD ¼12.0) for ketamine

and 5.7 (SD ¼10.2) for

placebo; in the thrice-weekly

groups, it was 17.7 (SD ¼7.3)

for ketamine and 3.1 (SD ¼

5.7) for placebo.

(Loo et al., 2016) Multiple crossover, double-blind

study with active

placebo, midazolam

TRD (MDD)

MADRS 20

15 Ketamine administered IV

(n¼4), IM (n¼5) or SC

(n¼6) injection. Dose

titration commenced at

0.1 mg/kg increasing by

0.1 mg/kg up to 0.5 mg/kg,

given in separate

treatment sessions

separated by 1 week,

with one random

placebo treatment

MADRS Twelve participants achieved

response and remission criteria,

achieved at doses as low as

0.1 mg/kg

IV, IM and SC routes resulted in

comparable

antidepressant effects

Fewest adverse effects were

noted with the SC route

(George et al., 2017) Randomized, active-placebo

controlled (midazolam) double-

blind, multiple-crossover study

with a 6-month follow-up

TRD (MDD)

Age 60

MADRS 20

14 Up to five subcutaneous

doses of ketamine (0.1,

0.2, 0.3, 0.4, and 0.5 mg/

kg) administered in

separate sessions

(1 week apart)

MADRS 7/14 RCT-phase completers

remitted with

ketamine treatment

5 remitted at doses below

0.5 mg/kg

Doses 0.2 mg/kg were

significantly more effective

than midazolam

(Arabzadeh et al., 2018) Parallel arm, randomized placebo-

controlled, double-blind add on

study to sertraline (150 mg/day)

MDD

HAM-D 20

81 Oral ketamine 50 mg/day

(2 25 mg /day

for 6 weeks)

HAM-D-17 Significant effect for

time treatment interaction on

the HAM-D scores, with

significant differences at all time

points post-treatment.

Early improvement was

significantly greater in the

ketamine group (85.4%)

compared to the placebo

group (42.5%).

(Daly et al., 2018) Fourteen site, doubly randomized,

placebo-controlled study

TRD (MDD)

QIDS-SR16 11

67 Intranasal (S)-ketamine 28 mg,

56 mg or 84 mg twice

weekly for two 1-week

periods followed by open

label extension

MADRS Reduction in MADRS score (both

periods combined) in all 3 (S)-

ketamine groups was superior to

placebo (28 mg: least-square

mean difference ¼4.2, SE ¼

(continued)

6 L. A. JELEN AND J. M. STONE

Table 1. Continued.

Study Design Patient group nDosing regime Outcome Antidepressant effects

2.09, p¼0.02; 56 mg: 6.3, SE¼

2.07, p¼0.001; 84 mg: 9.0, SE

¼2.1, p<0.001).

Significant ascending dose-

response relationship (p<0.001)

(Canuso et al., 2018) Eleven site, parallel arm, randomized

placebo-controlled, double-blind

study (in addition to standard-of-

care treatment)

TRD (MDD)

MADRS 22

68 Intranasal (S)-ketamine 84 mg

twice weekly for 4 weeks

MADRS Significantly greater

improvement in MADRS score

was observed (S)-ketamine group

compared with the placebo

group at 4 h (least-square mean

difference ¼5.3, SE ¼2.10;

effect size ¼0.61) and at 24 h

(least-square mean difference ¼

7.2, SE ¼2.85; effect size

¼0.65)

Difference not significant at day

25 (least-square mean difference

¼4.5, SE ¼3.14; effect size

¼0.35).

(Popova et al., 2019) 39 site, parallel arm, randomized

placebo-controlled, a double-blind

study in addition to newly

initiated antidepressant

TRD (MDD)

IDS-C 34

227 Intranasal (S)-ketamine 56 mg

or 84 mg twice weekly

for 4 weeks

MADRS Reduction in MADRS score with

(S)-ketamine þantidepressant

was significantly greater than

with placebo þantidepressant at

day 28 (least-square mean

difference ¼4.0, SE ¼1.69)

(Daly et al., 2019) 99 site, double-blind, randomized

withdrawal study, in addition to

oral antidepressant

TRD (MDD)

MADRS 28

297 Intranasal (S)-ketamine 56 mg

or 84 mg twice weekly for

16 weeks followed by

randomized withdrawal

phase (to continue (S)-

ketamine or switch

to placebo)

MADRS 176/297 in randomized

maintenance phase achieved

stable remission. 24 (26.7%) in

the (S)-ketamine þantidepressant

group and 39 (45.3%) in the

placebo þantidepressant group

experienced relapse (log-rank

p¼0.003, NNT¼6)

121 achieved stable response. 16

(25.8%) in the (S)-

ketamine þantidepressant group

and 34 (57.6%) in the

placebo þantidepressant group

experienced relapse (log-rank

p<0 .001, NNT¼4)

(Fedgchin et al., 2019) Multicentre, parallel arm, randomized

placebo-controlled, double-blind

study, in addition to oral

antidepressant

TRD (MDD)

MADRS 28

346 Intranasal (S)-ketamine 56 mg

or 84 mg twice weekly

for 4 weeks

MADRS No significant difference in

change in MADRS at 4 weeks

between (S)-ketamine

84 mg þantidepressant

compared with

placebo þantidepressant (least-

square mean difference –3.2,

p¼0.088)

(continued)

INTERNATIONAL REVIEW OF PSYCHIATRY 7

lasting up to 1 week (Wilkinson et al., 2018).

Reported effect sizes were moderate to large

(Cohen’sd¼0.48–0.85) at all examined time points

after dosing.

Although most of the studies of IV ketamine in

depression have investigated racemic ketamine,

others specifically exploring the antidepressant

effects of the component (S)- and (R)-enantiomers

have also been performed. In a first proof-of-con-

cept study, IV (S)-ketamine at doses of 0.2 mg/kg

and 0.4 mg/kg over 40 min led to rapid and robust

antidepressant effects in individuals with TRD

(Singh, Fedgchin, Daly, Xi, et al., 2016). However,

dose-dependent treatment-emergent side-effects

including headache, nausea, and dissociation were

still present. The authors suggest that the lower

dose of (S)-ketamine may allow for better tolerabil-

ity while maintaining efficacy, as improvements in

depressive symptoms were not significantly different

between the two tested doses. More recently, find-

ings from a small open-label pilot study of (R)-

ketamine in TRD have been published (Leal et al.,

2020). Here, seven individuals received a single IV

infusion of 0.5 mg/kg (R)-ketamine over 40 min.

There was a significant reduction in mean MADRS

scores from 30.7 at baseline to 10.4 at 1 day after

the infusion with a 71% response rate at day 1 and

57% at day 7. Importantly, dissociative effects were

nearly absent, alongside minimal haemodynamic

parameter changes. Although very interesting, these

results from a small open-label study should be

interpreted with caution, and a larger RCT is

needed to confirm these putative findings.

What is the evidence for alternative routes of

administration?

While most of the RCTs of ketamine have investi-

gated IV administration, it is possible to administer

ketamine via a range of other routes including oral,

intranasal, subcutaneous or intramuscular.

Comparatively fewer RCTs have fully evaluated these

options at this time.

Lapidus et al. (2014) examined the effect of a

single dose of 50 mg of racemic ketamine adminis-

tered intranasally in 20 subjects with treatment-

resistant MDD. A significant antidepressant effect

was detected as early as 40 min and after 24 h, 8/18

patients had responded to ketamine, while only 1/

18 to placebo. Furthermore, there were minimal

psychotomimetic or dissociative effects noted, with-

out clinically significant changes in haemodynamic

Table 1. Continued.

Study Design Patient group nDosing regime Outcome Antidepressant effects

(Domany et al., 2019) Parallel arm, randomized placebo-

controlled, double-blind study add

on to antidepressant treatment

TRD (MDD)

MADRS 19

41 Oral ketamine 1 mg/kg 3

times a week over 6 weeks

MADRS The reduction in MADRS score on

day 21 was 12.75 in the

ketamine group versus 2.49

points with placebo (p<0.001)

Six participants in the ketamine

group (27.3%) achieved remission

compared with none of the

controls (p<0.05)

NNT for remission was 3.7

(Ionescu et al., 2019) Parallel arm, randomized placebo-

controlled, double-blind study,

add on to stable antidepressant

treatment for 4 weeks

TRD (MDD)

HAM-D 20

26 IV ketamine infusion

(0.5 mg/kg over 45 min) 2

times a week for 3 weeks

HAM-D-28 No differences in depression

severity or suicidal ideation

between placebo and ketamine

(p¼0.47 and p¼0.32,

respectively) during the

infusion phase.

(Ochs-Ross et al., 2020) Parallel arm, randomized placebo-

controlled, double-blind study in

addition to oral antidepressant

TRD (MDD)

Age 65 years

138 Flexibly dosed (28 mg, 56 mg,

or 84 mg) (S)-ketamine

nasal spray twice weekly

for 4 weeks

MADRS No significant difference in

primary outcome (change in

MADRS at 4 weeks) between (S)-

ketamine þantidepressant vs

placebo þantidepressant

MDD: major depressive disorder; TRD: treatment-resistant depression; BD: bipolar depression; HAM-D: Hamilton depression rating scale; MADRS: Montgomery Asberg Depression Rating Scale; BSI: Beck Scale for

Suicide Ideation; SSI: The Scale for Suicidal Ideation.

8 L. A. JELEN AND J. M. STONE

measures. In contrast, another group found that

self-administered intranasal ketamine at 10 10 mg

doses separated by 5 min was poorly tolerated, with

significant cardiovascular, psychotomimetic and

neurological side effects and significant inter-indi-

vidual variation in pharmacokinetic parameters

(G

alvez et al., 2018). They concluded that this route

of administration was not useful when using their

device and dosing regime.

Following the initial study of IV (S)-ketamine, a

fixed-dose (S)-ketamine nasal spray has been devel-

oped and investigated in TRD. Results from several

phase II and phase III RCTs demonstrated that intra-

nasal (S)-ketamine in addition to an oral antidepres-

sant showed a significant benefit over placebo plus an

oral antidepressant in individuals with TRD (Canuso

et al., 2018; Daly et al., 2018,2019; Popova et al.,

2019), however, other studies have failed to demon-

strate positive results (Fedgchin et al., 2019; Ochs-

Ross et al., 2020). The (S)-ketamine nasal spray,

Spravato

, has now been approved for adults with

TRD, when used in combination with an oral anti-

depressant, by the US Food and Drug Administration

and subsequently by the European Medicines Agency.

Despite these regulatory approvals, there are still

some questions surrounding uncertainty of efficacy,

long-term safety and potential for abuse which may

limit widespread use (Kryst et al., 2020;

Turner, 2019).

There have been two placebo-controlled RCTs of

adjunctive oral ketamine to standard antidepressant

medications at doses of 50 mg a day over 6 weeks

(Arabzadeh et al., 2018) and 1 mg/kg three times a

week over 6 weeks (Domany et al., 2019). Results

from both studies suggest that oral ketamine has

significant antidepressant effects and is generally

well-tolerated, however, the effects are not as rapid

as those seen with IV ketamine (Arabzadeh et al.,

2018; Domany et al., 2019). For subcutaneous and

IM routes the evidence base is limited, in terms of

placebo-controlled RCTs. A small crossover study

compared IV, SC, and IM and found the anti-

depressant effects were comparable across the inves-

tigated routes of administration, although fewer

adverse effects were reported with the SC route

(Loo et al., 2016). A further multiple crossover

RCT examined differing SC doses of ketamine in

TRD ranging from 0.1 mg/kg to 0.5 mg/kg and

reported that doses 0.2 mg/kg were significantly

more effective than the active comparator midazo-

lam (George et al., 2017).

How can the response to ketamine

be maintained?

Although the majority of studies have demonstrated a

rapid and robust antidepressant response following a

single dose of ketamine, in most patients the anti-

depressant effects following a single administration

are not sustained beyond seven days (Kishimoto

et al., 2016). Other studies have examined whether

the antidepressant effects of ketamine could be

extended with repeated administration. In the first

double-blind RCT of repeated ketamine administra-

tion, it was demonstrated that twice- or thrice-weekly

administration of IV ketamine (0.5 mg/kg over

40 min) was sufficient to maintain antidepressant effi-

cacy over 15 days in individuals with TRD (Singh,

Fedgchin, Daly, De Boer, et al., 2016). In contrast, in

a more recent double-blind RCT, where 26 individu-

als with TRD and current, chronic suicidal ideation

were randomized to six ketamine infusions (0.5 mg/kg

over 45 min) or saline placebo over 3 weeks, at the

end of the infusion phase differences in depression

severity and suicidality were not significant between

ketamine or placebo (Ionescu et al., 2019). The

authors suggest that the traditional ketamine dose

used may not have been sufficient to produce an

improvement in their study sample that had high lev-

els of chronicity, treatment-resistance and concomi-

tant medications, and that an increase in dose beyond

0.5 mg/kg may be required to achieve clinically sig-

nificant effects in this group.

Although a large number of private clinics are

offering ketamine infusion treatments across the

United States (Ketamine-Clinics-Directory, 2020), the

use of repeated IV ketamine infusions may not always

be the most practical, considering the potential

resources required that might limit the capacity and

scalability of services. Other routes including oral and

intranasal may prove to be more feasible alternatives

when it comes to repeat administrations and mainten-

ance of response. MDD subjects receiving oral keta-

mine 50 mg/day as an adjunct to sertraline showed a

significantly greater reduction in depressive symptoms

at a 6 week time point compared to those randomized

to receive placebo and sertraline (Arabzadeh et al.,

2018). In another RCT of repeated oral ketamine for

TRD, 33 individuals were randomized to receive

1 mg/kg oral ketamine or placebo thrice weekly for

21 days (Domany et al., 2019). The ketamine treated

group had a significantly greater reduction in

MADRS score on day 21 versus placebo, with 27.3%

achieving remission compared to none of the

INTERNATIONAL REVIEW OF PSYCHIATRY 9

controls. Importantly side-effects were mild

and transient.

In the RCTs of intranasal (S)-ketamine in TRD

(plus an oral antidepressant), utilizing 28–84 mg

twice-weekly dosing, significant reductions in depres-

sive symptoms have been shown at 1 week (Daly

et al., 2018), day 11 (Canuso et al., 2018) and up to

4 weeks (Popova et al., 2019), however other studies

have failed to show significant differences at the

4 week time point (Canuso et al., 2018; Fedgchin

et al., 2019; Ochs-Ross et al., 2020). In a large study

examining intranasal (S)-ketamine (56 mg or 84 mg

twice weekly) plus oral antidepressant treatment for

16 weeks followed by a randomized withdrawal phase

(to continue with (S)-ketamine or switch to placebo),

of the 297 adults with TRD who were randomized in

the maintenance phase, those who continued treat-

ment with intermittently administered (S)-ketamine

nasal spray plus an oral antidepressant had a signifi-

cantly delayed time to relapse compared to those

treated with placebo nasal spray and oral antidepres-

sant (Daly et al., 2019). This suggests that continued

maintenance treatment with (S)-ketamine nasal spray

plus an oral antidepressant can sustain antidepressant

effects in individuals with TRD to a greater degree

than oral antidepressant treatment alone.

What are the potential adverse effects

of ketamine?

Acute side-effects following subanaesthetic ketamine

treatment are relatively common, especially when

delivered intravenously (Short et al., 2018). However,

most of these effects are mild and transient, occurring

during the infusion period and resolving shortly after

dose administration. Of note, these include elevated

blood pressure (asymptomatic), nausea, headache,

blurred vision, perceptual disturbance, drowsiness,

dizziness, dissociation and anxiety (Acevedo-Diaz

et al., 2020; Short et al., 2018).

Blood pressure should be assessed before treatment

with ketamine and individuals with comorbid hyper-

tension should have their blood pressure management

optimized before commencing ketamine. Blood pres-

sure should be monitored after dosing until the blood

pressure returns to acceptable levels. In an analysis of

684 infusions in 66 patients, with ketamine adminis-

tered IV at 0.5 mg/kg over 40 min, the biggest

increases in blood pressure were measured at 30 min

(systolic 3.28 mmHg, diastolic 3.17 mmHg) (Riva-

Posse et al., 2018). Although hypertensive patients

had higher blood pressure peaks during the infusions,

values returned to baseline during post-infusion mon-

itoring at 70 min. For patients with congestive cardiac

failure or a history of cerebrovascular accident par-

ticular caution should be taken or alternative treat-

ments considered (Short et al., 2018).

Another consideration is the effect of ketamine on

cognition, particularly after repeated administration.

An extensive review of the effects of acute ketamine

on the memory of healthy volunteers and of repeated

doses of ketamine in recreational users highlighted

that non-chronic usage of ketamine impairs the

manipulation of information in working memory and

produces transient decrements in the encoding of

information into episodic memory (Morgan &

Curran, 2006). Further, chronic, frequent recreational

use may be associated with more marked deficits in

working and episodic memory (Morgan & Curran,

2012). These are important harms to be aware of,

however, findings from studying cognitive side-effects

in frequent or addicted recreational ketamine users

should not be extrapolated to patients receiving care-

fully prescribed doses in a controlled clinical setting.

In a clinical study examining the effects of repeated

ketamine infusions in TRD, no patients reported any

cognitive deficits in excess of that reported at baseline

(Aan Het Rot et al., 2010). However, a limitation of

this study and other studies of ketamine treatment in

depression is a lack of formal cognitive testing (Short

et al., 2018).

In chronic, frequent use in recreational users, a

major physical harm is ketamine-induced urinary

tract symptoms and ulcerative cystitis (Morgan &

Curran, 2012). The aetiology of ketamine-induced

ulcerative cystitis is unclear, however, it appears to be

particularly observed in individuals with a history of

chronic, daily abuse use of the drug (Shahani et al.,

2007). It should be noted that recreational ketamine

consumption tends to be several orders of magnitude

higher (one survey reported 34% of users reported

use of 1 g or more in a typical session(Winstock et al.,

2012)) than the doses prescribed in the clinical setting

for depression. Although adverse effects of long-term

ketamine use on the bladder would not necessarily be

expected with the therapeutic dosing and frequency

used in the treatment of depression, the lack of

assessment of urinary symptoms has been another

limitation in RCTs of ketamine (Short et al., 2018). In

the (S)-ketamine nasal spray clinical program, there

were no reported cases of ulcerative or interstitial

cystitis, however (S)-ketamine-treated patients had a

higher incidence of lower urinary tract adverse events

(FDA, 2019), and the recommendation to monitor for

10 L. A. JELEN AND J. M. STONE

urinary tract and bladder symptoms during the course

of treatment has appropriately been added to the

summary of product characteristics (EMC, 2019).

Side-effects associated with intranasal (S)-ketamine

administration appear similar to those seen with

racemic ketamine (Swainson et al., 2019). However,

there appear to be important differences in adverse

effects between ketamine’s enantiomers. In a healthy

volunteer study while (S)-ketamine administration

produced acute psychosis-like reactions, (R)-ketamine

did not produce any psychotic symptoms but instead

a state of relaxation and a feeling of well-being

(Vollenweider et al., 1997). More recently, a small

pilot trial of (R)-ketamine in TRD reported minimal

dissociative symptoms without clinically significant

changes in hemodynamic measures (Leal et al., 2020).

A direct comparison study of the safety and efficacy

of (R)-ketamine and (S)-ketamine in TRD is yet to

be performed.

What is the abuse potential of ketamine?

Alongside its clinical applications ketamine is also

widely used recreationally (Sassano-Higgins et al.,

2016). At subanaesthetic doses, users may experience

psychedelic-like effects (including altered perceptions,

synaesthesia, derealization and depersonalization),

while at higher doses users may experience more pro-

nounced out-of-body experiences including a loss of

sense of space and time. Ketamine is commonly used

recreationally by snorting the powdered form but

may also be used intravenously or intramuscularly

(Bokor & Anderson, 2014).

Ketamine, especially when used in large and fre-

quent doses has the potential to lead to tolerance and

addiction (Sassano-Higgins et al., 2016). The mecha-

nisms underlying the reinforcing effects of ketamine

may include pleasant sensations or temporary relief of

negative emotions resulting from its dissociative

effects, actions on dopaminergic (Kokkinou et al.,

2018) and mu-opioid systems (Williams et al., 2018;

Zanos et al., 2018), alongside reward-circuitry activa-

tion (Sterpenich et al., 2019). While there are reports

of recreational ketamine users describing withdrawal

symptoms including anxiety, shaking, sweating and

palpitations when they stopped using (Morgan &

Curran, 2012; Chen et al., 2014), the true prevalence,

severity and duration of such symptoms is not

known. Unlike opiate addiction, there is no definitive

evidence to suggest physical dependence and a spe-

cific ketamine withdrawal syndrome has not yet been

described. In fact, ketamine treatment delivered in

controlled clinical settings is also being investigated as

a treatment to reduce alcohol, cocaine or opioid

dependence (Jones et al., 2018).

In an analysis of 11 healthy volunteer studies,

involving repeated ketamine infusions in carefully

monitored clinical research studies, there was no evi-

dence of behavioural sensitization (Cho et al., 2005).

Although this work suggests repeated low dose keta-

mine infusions can be used safely in clinical settings,

it is important to note these studies were conducted

in non-depressed rather than depressed patients that

may have differences in reward-circuitry (Quevedo

et al., 2017). In longer-term follow-up data of

depressed subjects receiving ketamine infusions in

clinical trials, there was no evidence of ketamine

abuse, increased drug cravings or substance abuse

(Wan et al., 2015). In the (S)-ketamine nasal spray

randomized withdrawal study (Daly et al., 2019), no

evidence of a distinct withdrawal syndrome was

observed in individuals with TRD during the 2 weeks

after cessation of (S)-ketamine (as assessed by the 20-

item Physician Withdrawal Checklist) and no adverse

events were reported by participants related to use or

abuse of ketamine. While these findings are reassur-

ing, there is still insufficient data examining repeated

prolonged use in this population and some have

argued for caution amongst clinicians until there is

further data on ketamine’s longer-term efficacy and

risks (Schatzberg, 2014).

The need for careful monitoring of depressed

patients receiving repeated ketamine treatment to

ensure personal safety (for example dosage, side-

effects and dependency) has been raised by patients

and carers (Jilka et al., 2019). It has been argued as

ketamine and intranasal (S)-ketamine become more

widely and frequently prescribed, a multi-drug moni-

toring system should be in place to help ensure safer

use, define less common side-effects and prevent

abuse (McShane, 2019).

What are the mechanisms of ketamine’s

antidepressant action?

The antidepressant effects of ketamine may be medi-

ated via blockade of NMDA receptors located on

GABAergic inhibitory interneurons that normally act

to suppress glutamate release from downstream gluta-

matergic neurons (Krystal et al., 2019). The preferen-

tial action of NMDA antagonists at GABAergic

interneurons is supported by work that found NMDA

receptor inhibition (via administration of the NMDA

antagonist MK801) predominately reduces the activity

INTERNATIONAL REVIEW OF PSYCHIATRY 11

of putative GABA interneurons and at delayed rate

increases the firing rate of pyramidal neurons

(Homayoun & Moghaddam, 2007). This disinhibition

hypothesis has been further supported by work dem-

onstrating that ketamine enhances glutamatergic

transmission, via pyramidal cells firing more action

potentials, indirectly by reducing synaptic GABAergic

inhibition (Gerhard et al., 2020; Widman &

McMahon, 2018). This disinhibition of glutamatergic

neurons results in an acute cortical glutamate surge

(Abdallah et al., 2018; Milak et al., 2016; Moghaddam

et al., 1997) and subsequent activation of post-synap-

tic a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic

acid (AMPA) receptors appears to be a crucial step,

leading to activation of neuroplastic signalling path-

ways and synaptogenesis (Lener et al., 2017)(Figure

1). The critical role of AMPA activation is supported

by findings from preclinical work demonstrating that

AMPA receptor antagonist administration blocks ket-

amine’s antidepressant effects (Koike et al., 2011;

Koike & Chaki, 2014; Maeng et al., 2008).

One of the key intracellular pathways implicated in

the antidepressant mechanism of ketamine is brain-

derived neurotrophic factor (BDNF)-tropomyosin kin-

ase B (TrkB) signalling, which has already been impli-

cated in the pathophysiology of depression and the

mechanism of action of currently prescribed antide-

pressants (Duman & Monteggia, 2006; Hashimoto

et al., 2004). Preclinical work has demonstrated that

the rapid antidepressant effects of ketamine are asso-

ciated with rapid synthesis and upregulation of BDNF

mediated by AMPA receptor activation (Autry et al.,

2011; Zhou et al., 2014). Ketamine-mediated antagon-

ism of postsynaptic NMDA receptors also leads to

augmentation of BDNF synthesis through deactivation

of eukaryotic elongation factor 2 (eEF2) kinase,

reduced eEF2 phosphorylation and subsequent de-

suppression of BDNF translation (Autry et al., 2011;

Monteggia et al., 2013). Further animal work has

shown that a TRkB antagonist was able to block the

antidepressant effects of both of ketamine’s enantiom-

ers (Yang et al., 2015). Interestingly, (R)-ketamine-

induced greater effects on reduced dendritic spine

density, BDNF–TrkB signalling and synaptogenesis

compared with (S)-ketamine (Yang et al., 2015).

The mammalian target of rapamycin complex 1

(mTORC1) and extracellular signal-regulated kinase

(ERK) are further signalling molecules implicated in

the antidepressant mechanism of ketamine, with key

roles in synaptic development and plasticity

(Mendoza et al., 2011; Ignacio et al., 2016). Animal

work has shown that ketamine administration rapidly

Figure 1. Proposed signalling pathways underlying antidepres-

sant effects of ketamine. Ketamine selectively blocks NMDA

receptors expressed on GABAergic inhibitory interneurons that

synapse on the dendrites, cell body and axon initial segment

of pyramidal neurons (Note, this simplified figure only shows

an example GABAergic interneuron synapsing on the axon ini-

tial segment). This leads to disinhibition of pyramidal neurons,

increased firing and evoked glutamate release. The resulting

glutamate surge stimulates postsynaptic AMPA receptors lead-

ing to increased release of BDNF that activates TrkB and sub-

sequent Akt/mTORC1 and MEK/ERK signalling pathways. This

ultimately leads to increased synthesis of proteins required for

synaptogenesis. Ketamine also suppresses resting postsynaptic

NMDA receptor activity, deactivating eEF2 kinase, resulting in

reduced eEF2 phosphorylation, augmentation of BDNF synthe-

sis and subsequent TrkB-mTORC1 activation.

12 L. A. JELEN AND J. M. STONE

activates the mTORC pathway leading to an increase

in synaptic signalling proteins and spine density (Li

et al., 2010). Moreover, administration of rapamycin,

an mTORC1 inhibitor, has been demonstrated to

block synaptogenesis and antidepressant-like effects

induced by ketamine. (Li et al., 2010,2011).

Considering ketamine’s enantiomers, additional pre-

clinical work has shown that the antidepressant-like

effects of (S)-ketamine but not (R)-ketamine were

blocked by mTORC1 inhibition and that the anti-

depressant-like effects of (R)-ketamine but not (S)-

ketamine were blocked by an ERK inhibitor suggest-

ing (R)-ketamine may cause a preferential activation

of the ERK signalling pathway (Yang, Ren,

et al., 2018).

mTORC signalling activation leads to the deactiva-

tion of glycogen synthase kinase-3 (GSK-3) and inhib-

ition of GSK-3 has been shown to be required for the

antidepressant-like effects of (R,S)-ketamine in a

rodent model (Beurel et al., 2011). Further preclinical

studies have demonstrated that ketamine administra-

tion in combination with lithium, a non-selective

GSK-3 inhibitor, resulted in rapid activation of

mTORC1 signalling, increased inhibition of GSK-3,

increased synaptic spine density and greater anti-

depressant-like responses (Liu et al., 2013), however,

clinical studies have not replicated these preclinical

findings (Costi et al., 2019; Xu et al., 2015).

Monoaminergic systems may also play a role in the

antidepressant mechanism of ketamine. Pre-clinical

studies have shown that ketamine’s antidepressant-

like effects are blocked by 5-HT depletion (Fukumoto

et al., 2016; Gigliucci et al., 2013) and that ketamine

also inhibits serotonin transporter (SERT) function

(Zhao & Sun, 2008). More specifically, increased 5-

HT release in the medial prefrontal cortex (mPFC)

through AMPA receptor signalling in the dorsal raphe

nucleus (Chaki & Fukumoto, 2019; Pham et al., 2017)

and subsequent 5-HT

activation with downstream

convergence on mTORC1 signalling, appears to be

another mechanism through which ketamine may

exert its antidepressant effects (Fukumoto et al.,

2018). A meta-analysis found ketamine administration

at subanaesthetic doses in rodents to be associated

with significantly increased levels of dopamine in

regions including the cortex, striatum and nucleus

accumbens across studies using microdialysis, high-

performance liquid chromatography and electrochem-

ical detection to measure extracellular and total

dopamine, compared to control conditions (Kokkinou

et al., 2018). Clinical work using PET imaging has

also demonstrated that acute ketamine administration

leads to increased dopamine release in the striatum in

humans (Smith et al., 1998; Vollenweider et al., 2000).

The exact role of the dopamine system in the anti-

depressant action of ketamine is yet to be fully eluci-

dated, however recent preclinical work has suggested

a key role for dopamine D

receptor activity in the

mPFC (Hare et al., 2019).

Alongside the monoaminergic system, ketamine

also interacts with opioid receptors, including mu,

kappa and to a lesser extent, delta-opioid receptors

(Zanos et al., 2018). Recent clinical work has sug-

gested that opioid system activation may be required

for the rapid-acting antidepressant effects of ketamine

(Williams et al., 2018). In this study, it was shown

that pre-treatment with the opioid receptor antagonist

naltrexone significantly blocked the antidepressant

effects of ketamine in TRD. However, this study was

limited by small sample size and lack of a placebo

control arm for the ketamine infusion. In contrast,

another clinical study found that naltrexone pre-treat-

ment did not reduce the antidepressant effects of

ketamine in subjects with comorbid depression and

alcohol use disorder (Yoon et al., 2019). While there

has been preclinical work that demonstrated pre-treat-

ment with naltrexone did not block the antidepres-

sant-like effects of ketamine in a rodent model of

depression (Zhang & Hashimoto, 2019), a further

rodent study showed that treatment with an opioid

receptor antagonist blocked ketamine’s antidepres-

sant-like behavioural effects and abolished ketamine’s

ability to reduce lateral habenula hyperactivity, while

administration of the mu-opioid agonist, morphine,

alone did not mimic either of these effects (Klein

et al., 2020). This suggests that ketamine is not simply

acting as a mu-opioid agonist, but that some mu-opi-

oid receptor activity may be necessary for NMDA

receptor antagonism.

The lateral habenula is a brain region involved in

regulating reward and abnormal increases in neural

activity in this region may signal down-regulation of

monoaminergic firing resulting in depressive symp-

tomatology including anhedonia and helplessness

(Gold & Kadriu, 2019). It has previously been shown

that inhibition of NMDA receptor-dependent activity

in the lateral habenula facilitates ketamine’s anti-

depressant-like actions in a rodent model of depres-

sion (Yang, Cui, et al., 2018). In brain regions

including the habenula, opioid receptors and NMDA

receptors are colocalized (Rodriguez-Munoz et al.,

2012) and it is suggested that the glutamatergic and

opioid systems may interact through direct ‘crosstalk’

(Chartoff & Connery, 2014).

INTERNATIONAL REVIEW OF PSYCHIATRY 13

The role of the opioid system in ketamine’s anti-

depressant effects remains controversial. While some

critics of ketamine therapy have claimed that keta-

mine seems to work mainly through stimulation of

opioid receptors, with a high potential for abuse

(Gøtzsche et al., 2019), evidence instead suggests that

ketamine is not an opioid per se, and its interactions

with the opioid system are more nuanced (Klein

et al., 2020; Malinow & Klein, 2020). While cautious

prescribing and monitoring of any drug with abuse

potential is required, it is important that ketamine is

not dismissed as merely an opioid and that we con-

tinue to explore the detailed nature of opioid signal-

ling in terms of its rapid antidepressant effects as this

could ultimately uncover novel pharmacological tar-

gets and antidepressant strategies.

Future directions

Although the discovery of ketamine’s rapid-acting

antidepressant effects has brought a fundamental

change in the treatment and understanding of the

neurobiology of depression, there are still a number

of unmet needs, both in terms of clinical and research

directions. Most of the evidence for the antidepressant

efficacy of ketamine and (S)-ketamine is via the IV

and intranasal routes. Further research is needed to

explore optimal dosing strategies, especially for routes

where less evidence is available such as sublingual,

oral and subcutaneous. Considering ketamine’s transi-

ent antidepressant effects, these alternative routes of

administration could prove to be more practical and

effective maintenance strategies. Further, there is a

need for careful monitoring and additional investiga-

tion into potential adverse effects associated with

long-term use as well as more data on long-term effi-

cacy and safety.

While the available evidence indicates that keta-

mine exerts rapid and robust antidepressant effects, it

should be noted that not all patients respond to keta-

mine treatment, with most trials reporting between a

50–70% response rate in TRD (Wan et al., 2015).

Further, other issues described in this review are that

of tolerability (eg. dissociative or psychotomimetic

effects) and safety (eg. CNS or urinary effects) with

short and long-term administration. Considering the

potential resources and costs required for ketamine

treatment (especially via the IV infusion route) and

necessary surveillance post-administration, the identi-

fication of predictive clinical/biomarkers of safety,

efficacy and tolerability in response to ketamine could

provide the opportunity to stratify subpopulations

with TRD who are more likely to benefit from treat-

ment (Rong et al., 2018). This could ultimately sup-

port a personalized medicine approach but also has

implications in terms of cost-effectiveness of deliver-

ing ketamine treatment. While a full discussion is

beyond the scope of this review, some candidate pre-

dictors of response to ketamine include clinical indi-

cators (i.e. high BMI and family history of an alcohol

use disorder) (Niciu et al., 2014), neuroimaging meas-

ures (i.e. anterior cingulate cortex activity (Salvadore

et al., 2009), glutamatergic metabolite levels

(Salvadore et al., 2012) and functional connectivity

(Gartner et al., 2019)), genetics (i.e. Val66Met BDNF

allele) (Laje et al., 2012), sleep (i.e. low baseline delta

sleep ratio) (Duncan et al., 2013) and cognitive func-

tion (i.e. slow processing speed) (Murrough, Burdick,

et al., 2015). Alterations in terms of inflammation and

metabolism in TRD are emerging as key areas of

investigation and indeed a recent systematic review

suggested that higher baseline interleukin-6 (IL-6) or

C-reactive protein (CRP)/high-sensitivity-CRP

(hsCRP) may predict response to medication with

anti-inflammatory characteristics, including ketamine

(Yang, Wardenaar, et al., 2019). However, at this

stage, none of these putative predictors have sufficient

positive predictive validity (PPV) to inform clinical

decision making.

In parallel to understanding potential predictors of

response, further work to understand the specific

mechanisms underlying ketamine’s rapid antidepres-

sant effects is needed. Not only will this further our

knowledge of the neurobiological processes underpin-

ning depression and antidepressant response to keta-

mine but will also help identify treatment targets for

use in the development of next-generation rapid-act-

ing treatments in depression that lack the dissociative

and psychotomimetic effects or abuse potential (Jelen

et al., 2018). Of particular note, (R)-ketamine and its

metabolite (2R,6R)-HNK have demonstrated more

potent and longer-lasting antidepressant-like effects

than (R,S)-ketamine and (S)-ketamine in preclinical

models (and also lack dissociative effects and abuse

potential in these models) (Yang, Yang, et al., 2019).

Clinical trials of (R)-ketamine and (2R,6R)-HNK are

either planned or underway ((Universal Trial

Number: U1111-1241-1005), (ChiCTR1800015879),

(Kraus et al., 2019)).

Conclusions

Ketamine has emerged as a novel antidepressant that

has effects in individuals otherwise resistant to

14 L. A. JELEN AND J. M. STONE

conventional antidepressants, with a remarkably rapid

speed of onset. As such, it represents one of the most

important breakthroughs in the treatment of depres-

sion in the last 50 years. However, maintenance of

response remains problematic and longer-term risks

associated with repeated administrations are less well

characterized. Although ketamine remains an off-label

treatment for TRD, the use of (S)-ketamine, plus an

oral antidepressant, has been approved for use in

TRD in the United States and Europe. However, con-

cerns regarding side-effects and abuse potential

remain, highlighting the need for careful monitoring

and further data on long-term safety. In the quest to

understand ketamine’s novel rapid-acting-antidepres-

sant mechanism, no one unique mechanism of action

has emerged as of yet, rather multiple, potentially

complementary, mechanistic pathways appear to exist.

Further understanding of the specific underlying

mechanisms of ketamine is critical as we seek to

develop alternative rapid-acting treatments in depres-

sion that may not share the same dissociative effects

or abuse potential.

Acknowledgments

The authors thank Ashleigh Earl for support in designing

the illustration presented in Figure 1.

Disclosure statement

This report represents independent research funded by the

National Institute for Health Research (NIHR) Biomedical

Research Centre at South London and Maudsley NHS

Foundation Trust and King’s College London. The views

expressed are those of the authors and not necessarily those

of the NHS, the NIHR, or the Department of Health.

Dr. Luke A. Jelen: The author declared no potential

conflicts of interest with respect to the research, authorship,

and/or publication of this article.

Dr. James M. Stone: In the last 3 years, JMS has been

PI or sub-investigator on studies sponsored by Takeda,

Janssen and Lundbeck Plc. He has attended an

Investigators’meeting run by Allergan Plc.

Funding

This research was funded by the National Institute for

Health Research (NIHR) Biomedical Research Centre at

South London and Maudsley NHS Foundation Trust and

King’s College London. Dr. Luke A. Jelen is a Medical

Research Council (MRC) Clinical Research Training Fellow

(MR/T028084/1).

ORCID

Luke A. Jelen http://orcid.org/0000-0001-6398-5239

James M. Stone http://orcid.org/0000-0003-3051-0135

References

Aan Het Rot, M., Collins, K. A., Murrough, J. W., Perez,

A. M., Reich, D. L., Charney, D. S., & Mathew, S. J.

(2010). Safety and efficacy of repeated-dose intravenous

ketamine for treatment-resistant depression. Biological

Psychiatry,67(2), 139–145. https://doi.org/10.1016/j.biop-

sych.2009.08.038

Abdallah, C. G., De Feyter, H. M., Averill, L. A., Jiang, L.,

Averill, C. L., Chowdhury, G. M. I., Purohit, P., de

Graaf, R. A., Esterlis, I., Juchem, C., Pittman, B. P.,

Krystal, J. H., Rothman, D. L., Sanacora, G., & Mason,

G. F. (2018). The effects of ketamine on prefrontal glu-

tamate neurotransmission in healthy and depressed sub-

jects. Neuropsychopharmacology,43(10), 2154–2160.

https://doi.org/10.1038/s41386-018-0136-3

Acevedo-Diaz, E. E., Cavanaugh, G. W., Greenstein, D.,

Kraus, C., Kadriu, B., Zarate, C. A., & Park, L. T. (2020).

Comprehensive assessment of side effects associated with

a single dose of ketamine in treatment-resistant depres-

sion. Journal of Affective Disorders,263, 568–575. https://

doi.org/10.1016/j.jad.2019.11.028

Al-Harbi, K. S. (2012). Treatment-resistant depression:

Therapeutic trends, challenges, and future directions.

Patient Preference and Adherence,6, 369–388. https://doi.

org/10.2147/PPA.S29716

Arabzadeh, S., Hakkikazazi, E., Shahmansouri, N.,

Tafakhori, A., Ghajar, A., Jafarinia, M., & Akhondzadeh,

S. (2018). Does oral administration of ketamine acceler-

ate response to treatment in major depressive disorder?

Results of a double-blind controlled trial. Journal of

Affective Disorders,235, 236–241. https://doi.org/10.1016/

j.jad.2018.02.056

Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los,

M. F., Cheng, P-f., Kavalali, E. T., & Monteggia, L. M.

(2011). NMDA receptor blockade at rest triggers rapid

behavioural antidepressant responses. Nature,475(7354),

91–95. https://doi.org/10.1038/nature10130

Berman, R. M., Cappiello, A., Anand, A., Oren, D. A.,

Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000).

Antidepressant effects of ketamine in depressed patients.

Biological Psychiatry,47(4), 351–354. https://doi.org/10.

1016/s0006-3223(99)00230-9

Beurel, E., Song, L., & Jope, R. S. (2011). Inhibition of

glycogen synthase kinase-3 is necessary for the rapid

antidepressant effect of ketamine in mice. Molecular

Psychiatry,16(11), 1068–1070. https://doi.org/10.1038/

mp.2011.47

Bokor, G., & Anderson, P. D. (2014). Ketamine: An update

on its abuse. Journal of Pharmacy Practice,27(6),

582–586. https://doi.org/10.1177/0897190014525754

Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane,

R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji,

H., & Drevets, W. C. (2018). Efficacy and safety of intra-

nasal esketamine for the rapid reduction of symptoms of

depression and suicidality in patients at imminent risk

for suicide: results of a double-blind, randomized,

INTERNATIONAL REVIEW OF PSYCHIATRY 15

placebo-controlled study. The American Journal of

Psychiatry,175(7), 620–630. https://doi.org/10.1176/appi.

ajp.2018.17060720

Cao, Z., Lin, C., & Ding, W. (2018). Identifying ketamine

responses in treatment-resistant depression using a wear-

able forehead EEG. IEEE Transactions on Biomedical

Engineering,66(6), 1668–1679.

Chaki, S., & Fukumoto, K. (2019). Role of serotonergic sys-

tem in the antidepressant actions of mGlu2/3 receptor

antagonists: Similarity to ketamine. International Journal

of Molecular Sciences,20(6), 1270. https://doi.org/10.

3390/ijms20061270

Chartoff, E. H., & Connery, H. S. (2014). It’s MORe excit-

ing than mu: Crosstalk between mu opioid receptors and

glutamatergic transmission in the mesolimbic dopamine

system. Frontiers in Pharmacology,5, 116.

Chen, M.-H., Li, C.-T., Lin, W.-C., Hong, C.-J., Tu, P.-C.,

Bai, Y.-M., Cheng, C.-M., & Su, T.-P. (2018). Persistent

antidepressant effect of low-dose ketamine and activation

in the supplementary motor area and anterior cingulate

cortex in treatment-resistant depression: A randomized

control study. Journal of Affective Disorders,225,

709–714. https://doi.org/10.1016/j.jad.2017.09.008

Chen, W. Y., Huang, M. C., & Lin, S. K. (2014). Gender

differences in subjective discontinuation symptoms asso-

ciated with ketamine use. Substance Abuse Treatment,

Prevention, and Policy,9, 39. https://doi.org/10.1186/

1747-597X-9-39

Cho, H.-S., D’Souza, D. C., Gueorguieva, R., Perry, E. B.,

Madonick, S., Karper, L. P., Abi-Dargham, A., Belger, A.,

Abi-Saab, W., Lipschitz, D., Bennet, A., Seibyl, J. P., &

Krystal, J. H. (2005). Absence of behavioral sensitization

in healthy human subjects following repeated exposure

to ketamine. Psychopharmacology,179(1), 136–143.

https://doi.org/10.1007/s00213-004-2066-5

Corssen, G., & Domino, E. F. (1966). Dissociative anesthe-

sia: Further pharmacologic studies and first clinical

experience with the phencyclidine derivative CI-581.

Anesthesia and Analgesia,45(1), 29–40.

Costi, S., Soleimani, L., Glasgow, A., Brallier, J., Spivack, J.,

Schwartz, J., Levitch, C. F., Richards, S., Hoch, M.,

Wade, E., Welch, A., Collins, K. A., Feder, A., Iosifescu,

D. V., Charney, D. S., & Murrough, J. W. (2019).

Lithium continuation therapy following ketamine in

patients with treatment resistant unipolar depression: A

randomized controlled trial. Neuropsychopharmacology,

44(10), 1812–1819. https://doi.org/10.1038/s41386-019-

0365-0

Daly, E. J., Singh, J. B., Fedgchin, M., Cooper, K., Lim, P.,

Shelton, R. C., Thase, M. E., Winokur, A., Van Nueten,

L., Manji, H., & Drevets, W. C. (2018). Efficacy and

safety of intranasal esketamine adjunctive to oral anti-

depressant therapy in treatment-resistant depression: A

randomized clinical trial. JAMA Psychiatry,75(2),

139–148. https://doi.org/10.1001/jamapsychiatry.2017.

3739

Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li,

X., Lane, R., Lim, P., Duca, A. R., Hough, D., Thase,

M. E., Zajecka, J., Winokur, A., Divacka, I., Fagiolini, A.,

Cubala, W. J., Bitter, I., Blier, P., Shelton, R. C., …

Singh, J. B. (2019). Efficacy of esketamine nasal spray

plus oral antidepressant treatment for relapse prevention

in patients with treatment-resistant depression: A

randomized clinical trial. JAMA Psychiatry,76(9), 893.

https://doi.org/10.1001/jamapsychiatry.2019.1189

Diazgranados, N., Ibrahim, L., Brutsche, N. E., Newberg,

A., Kronstein, P., Khalife, S., Kammerer, W. A.,

Quezado, Z., Luckenbaugh, D. A., Salvadore, G.,

Machado-Vieira, R., Manji, H. K., & Zarate, C. A.

(2010). A randomized add-on trial of an N-methyl-D-

aspartate antagonist in treatment-resistant bipolar

depression. Archives of General Psychiatry,67(8),

793–802. https://doi.org/10.1001/archgenpsychiatry.2010.

Domany, Y., Bleich-Cohen, M., Tarrasch, R., Meidan, R.,

Litvak-Lazar, O., Stoppleman, N., Schreiber, S., Bloch,

M., Hendler, T., & Sharon, H. (2019). Repeated oral

ketamine for out-patient treatment of resistant depres-

sion: Randomised, double-blind, placebo-controlled,

proof-of-concept study. The British Journal of Psychiatry,

214(1), 20–26. https://doi.org/10.1192/bjp.2018.196

Domino, E. F. (1980). History and pharmacology of PCP

and PCP-related analogs. Journal of Psychedelic Drugs,

12(3–4), 223–227. https://doi.org/10.1080/02791072.1980.

10471430

Domino, E. F. (2010). Taming the ketamine tiger. 1965.

Anesthesiology, 113(3), 678–684. https://doi.org/10.1097/

ALN.0b013e3181ed09a2

Downey, D., Dutta, A., McKie, S., Dawson, G. R., Dourish,

C. T., Craig, K., Smith, M. A., McCarthy, D. J., Harmer,

C. J., Goodwin, G. M., Williams, S., & Deakin, J. F. W.

(2016). Comparing the actions of lanicemine and keta-

mine in depression: Key role of the anterior cingulate.

European Neuropsychopharmacology: The Journal of the

European College of Neuropsychopharmacology,26(6),

994–1003. https://doi.org/10.1016/j.euroneuro.2016.03.006

Duman, R. S., & Monteggia, L. M. (2006). A neurotrophic

model for stress-related mood disorders. Biological

Psychiatry,59(12), 1116–1127. https://doi.org/10.1016/j.

biopsych.2006.02.013

Duncan, W. C., Selter, J., Brutsche, N., Sarasso, S., &

Zarate, C. A. (2013). Baseline delta sleep ratio predicts

acute ketamine mood response in major depressive dis-

order. Journal of Affective Disorders,145(1), 115–119.

https://doi.org/10.1016/j.jad.2012.05.042

Ebert, B., Mikkelsen, S., Thorkildsen, C., & Borgbjerg, F. M.

(1997). Norketamine, the main metabolite of ketamine, is

a non-competitive NMDA receptor antagonist in the rat

cortex and spinal cord. European Journal of

Pharmacology,333(1), 99–104. https://doi.org/10.1016/

s0014-2999(97)01116-3

EMC. (2019). Spravato 28 mg nasal spray, solution.

Summary of product characteristics. Medicines. https://

www.medicines.org.uk/emc/product/10977/smpc

Fava, M., Freeman, M. P., Flynn, M., Judge, H., Hoeppner,

B. B., Cusin, C., Ionescu, D. F., Mathew, S. J., Chang,

L. C., Iosifescu, D. V., Murrough, J., Debattista, C.,

Schatzberg, A. F., Trivedi, M. H., Jha, M. K., Sanacora,

G., Wilkinson, S. T., & Papakostas, G. I. (2020). Double-

blind, placebo-controlled, dose-ranging trial of intraven-

ous ketamine as adjunctive therapy in treatment-resistant

depression (TRD). Molecular Psychiatry,25(7),

1592–1603. https://doi.org/10.1038/s41380-018-0256-5

16 L. A. JELEN AND J. M. STONE

FDA. (2019). Efficacy, safety, and risk-benefit profile of New

Drug Application (NDA) 211243, esketamine 28 mg single-

use nasal spray device, submitted by Janssen

Pharmaceuticals, Inc., for the treatment of treatment-

resistant depression. Federal Drug Administration.

Fedgchin, M., Trivedi, M., Daly, E. J., Melkote, R., Lane, R.,

Lim, P., Vitagliano, D., Blier, P., Fava, M., Liebowitz, M.,

Ravindran, A., Gaillard, R., Ameele, H. V. D., Preskorn,

S., Manji, H., Hough, D., Drevets, W. C., & Singh, J. B.

(2019). Efficacy and safety of fixed-dose esketamine nasal

spray combined with a new oral antidepressant in treat-

ment-resistant depression: Results of a randomized, dou-

ble-blind, active-controlled study (TRANSFORM-1). The

International Journal of Neuropsychopharmacology,

22(10), 616–630. https://doi.org/10.1093/ijnp/pyz039

Fontana, A. (1974). Terapia atidepresiva con ketamine. Acta

Psiquiatrica y Psicologica de America Latina,20, 32.

Fukumoto, K., Fogac¸a, M. V., Liu, R.-J., Duman, C., Kato,

T., Li, X.-Y., & Duman, R. S. (2019). Activity-dependent

brain-derived neurotrophic factor signaling is required

for the antidepressant actions of (2R,6R)-hydroxynorket-

amine. Proceedings of the National Academy of Sciences

of the United States of America,116(1), 297–302. https://

doi.org/10.1073/pnas.1814709116

Fukumoto, K., Iijima, M., & Chaki, S. (2016). The anti-

depressant effects of an mGlu2/3 receptor antagonist and

ketamine require AMPA receptor stimulation in the

mPFC and subsequent activation of the 5-HT neurons in

the DRN. Neuropsychopharmacology,41(4), 1046–1056.

https://doi.org/10.1038/npp.2015.233

Fukumoto, K., Iijima, M., Funakoshi, T., & Chaki, S.

(2018). Role of 5-HT1A receptor stimulation in the med-

ial prefrontal cortex in the sustained antidepressant

effects of ketamine. The International Journal of

Neuropsychopharmacology,21(4), 371–381. https://doi.

org/10.1093/ijnp/pyx116

G

alvez, V., Li, A., Huggins, C., Glue, P., Martin, D.,

Somogyi, A. A., Alonzo, A., Rodgers, A., Mitchell, P. B.,

& Loo, C. K. (2018). Repeated intranasal ketamine for

treatment-resistant depression –the way to go? Results

from a pilot randomised controlled trial. Journal of

Psychopharmacology,32(4), 397–407. https://doi.org/10.

1177/0269881118760660

Gartner, M., Aust, S., & Bajbouj, M. (2019). Functional

connectivity between prefrontal cortex and subgenual

cingulate predicts antidepressant effects of ketamine.

European Neuropsychopharmacology.29(4), 501–508.

https://doi.org/10.1016/j.euroneuro.2019.02.008

George, D., G

alvez, V., Martin, D., Kumar, D., Leyden, J.,

Hadzi-Pavlovic, D., Harper, S., Brodaty, H., Glue, P.,

Taylor, R., Mitchell, P. B., & Loo, C. K. (2017). Pilot

randomized controlled trial of titrated subcutaneous

ketamine in older patients with treatment-resistant

depression. The American Journal of Geriatric Psychiatry,

25(11), 1199–1209. https://doi.org/10.1016/j.jagp.2017.06.

007

Gerhard, D. M., Pothula, S., Liu, R.-J., Wu, M., Li, X.-Y.,

Girgenti, M. J., Taylor, S. R., Duman, C. H., Delpire, E.,

Picciotto, M., Wohleb, E. S., & Duman, R. S. (2020).

GABA interneurons are the cellular trigger for ketamine’s

rapid antidepressant actions. The Journal of Clinical

Investigation,130(3), 1336–1349. https://doi.org/10.1172/

JCI130808

Gigliucci, V., O’Dowd, G., Casey, S., Egan, D., Gibney, S.,

& Harkin, A. (2013). Ketamine elicits sustained anti-

depressant-like activity via a serotonin-dependent mech-

anism. Psychopharmacology,228(1), 157–166. https://doi.

org/10.1007/s00213-013-3024-x

Gold, P. W., & Kadriu, B. (2019). A major role for the lat-

eral habenula in depressive illness: Physiologic and

molecular mechanisms. Frontiers in Psychiatry,10:320.

https://doi.org/10.3389/fpsyt.2019.00320

Gøtzsche, P. C., Hengartner, M. P., Davies, J. (2019). Rapid

response: Re: Esketamine for treatment resistant depres-

sion. Esketamine for depression? No thanks, please. BMJ.

https://www.bmj.com/content/366/bmj.l5572/rr-0

Grunebaum, M. F., Galfalvy, H. C., Choo, T.-H., Keilp,

J. G., Moitra, V. K., Parris, M. S., Marver, J. E., Burke,

A. K., Milak, M. S., Sublette, M. E., Oquendo, M. A., &

Mann, J. J. (2018). Ketamine for rapid reduction of sui-

cidal thoughts in major depression: A midazolam-con-

trolled randomized clinical trial. The American Journal of

Psychiatry,175(4), 327–335. https://doi.org/10.1176/appi.

ajp.2017.17060647

Hare, B. D., Shinohara, R., Liu, R. J., Pothula, S., DiLeone,

R. J., & Duman, R. S. (2019). Optogenetic stimulation of

medial prefrontal cortex Drd1 neurons produces rapid

and long-lasting antidepressant effects. Nature

Communications,10(1), 223. https://doi.org/10.1038/

s41467-018-08168-9

Hashimoto, K. (2020). Molecular mechanisms of the rapid-

acting and long-lasting antidepressant actions of (R)-

ketamine. Biochemical Pharmacology,177, 113935.

https://doi.org/10.1016/j.bcp.2020.113935

Hashimoto, K., Shimizu, E., & Iyo, M. (2004). Critical role

of brain-derived neurotrophic factor in mood disorders.

Brain Research Reviews,45(2), 104–114. https://doi.org/

10.1016/j.brainresrev.2004.02.003

Homayoun, H., & Moghaddam, B. (2007). NMDA receptor

hypofunction produces opposite effects on prefrontal

cortex interneurons and pyramidal neurons. The Journal

of Neuroscience,27(43), 11496–11500. https://doi.org/10.

1523/JNEUROSCI.2213-07.2007

Hu, Y.-D., Xiang, Y.-T., Fang, J.-X., Zu, S., Sha, S., Shi, H.,

Ungvari, G. S., Correll, C. U., Chiu, H. F. K., Xue, Y.,

Tian, T.-F., Wu, A.-S., Ma, X., & Wang, G. (2016).

Single i.v. ketamine augmentation of newly initiated esci-

talopram for major depression: Results from a random-

ized, placebo-controlled 4-week study. Psychological

Medicine,46(3), 623–635. https://doi.org/10.1017/

S0033291715002159

Ignacio, Z. M., R

eus, G. Z., Arent, C. O., Abelaira, H. M.,

Pitcher, M. R., & Quevedo, J. (2016) New perspectives

on the involvement of mTOR in depression as well as in

the action of antidepressant drugs. British journal of clin-

ical pharmacology, 82(5), 1280–1290.

Ionescu, D. F., Bentley, K. H., Eikermann, M., Taylor, N.,

Akeju, O., Swee, M. B., Pavone, K. J., Petrie, S. R.,

Dording, C., Mischoulon, D., Alpert, J. E., Brown, E. N.,

Baer, L., Nock, M. K., Fava, M., & Cusin, C. (2019).

Repeat-dose ketamine augmentation for treatment-resist-

ant depression with chronic suicidal ideation: A random-

ized, double blind, placebo controlled trial. Journal of

INTERNATIONAL REVIEW OF PSYCHIATRY 17

Affective Disorders,243, 516–524. https://doi.org/10.1016/

j.jad.2018.09.037

Jelen, L. A., King, S., & Stone, J. M. (2018). Alternatives to

ketamine in depression: State-of-the-art and future per-

spectives. Therapeutic Advances in Psychopharmacology,

8(3), 95–98. https://doi.org/10.1177/2045125317749456

Jelen, L. A., Young, A. H., & Stone, J. M. (2020). Ketamine:

A tale of two enantiomers. Journal of

Psychopharmacology. Advance online publication. https://

doi.org/10.1177/0269881120959644

Jilka, S., Murray, C., Wieczorek, A., Griffiths, H., Wykes,

T., & McShane, R. (2019). Exploring patients’and carers’

views about the clinical use of ketamine to inform policy

and practical decisions: Mixed-methods study. BJPsych

Open,5(5), e62. https://doi.org/10.1192/bjo.2019.52

Jones, J. L., Mateus, C. F., Malcolm, R. J., Brady, K. T., &

Back, S. E. (2018). Efficacy of ketamine in the treatment

of substance use disorders: A systematic review. Frontiers

in Psychiatry,9, 277. https://doi.org/10.3389/fpsyt.2018.

00277

Ketamine-Clinics-Directory. (2020). Ketamine Clinics

Directory. https://ketamineclinicsdirectory.com

Khorramzadeh, E., & Lotfy, A. O. (1973). The use of keta-

mine in psychiatry. Psychosomatics,14(6), 344–346.

https://doi.org/10.1016/S0033-3182(73)71306-2

Kishimoto, T., Chawla, J. M., Hagi, K., Zarate, C. A., Kane,

J. M., Bauer, M., & Correll, C. U. (2016). Single-dose

infusion ketamine and non-ketamine N-methyl-d-aspar-

tate receptor antagonists for unipolar and bipolar depres-

sion: A meta-analysis of efficacy, safety and time

trajectories. Psychological Medicine,46(7), 1459–1472.

https://doi.org/10.1017/S0033291716000064

Klein, M. E., Chandra, J., Sheriff, S., & Malinow, R. (2020).

Opioid system is necessary but not sufficient for antide-

pressive actions of ketamine in rodents. Proceedings of

the National Academy of Sciences of the United States of

America,117(5), 2656–2662. https://doi.org/10.1073/pnas.

1916570117

Koike, H., & Chaki, S. (2014). Requirement of AMPA

receptor stimulation for the sustained antidepressant

activity of ketamine and LY341495 during the forced

swim test in rats. Behavioural Brain Research,271,

111–115. https://doi.org/10.1016/j.bbr.2014.05.065

Koike, H., Iijima, M., & Chaki, S. (2011). Involvement of

AMPA receptor in both the rapid and sustained anti-

depressant-like effects of ketamine in animal models of

depression. Behavioural Brain Research,224(1), 107–111.

https://doi.org/10.1016/j.bbr.2011.05.035

Kokkinou, M., Ashok, A. H., & Howes, O. D. (2018). The

effects of ketamine on dopaminergic function: Meta-ana-

lysis and review of the implications for neuropsychiatric

disorders. Molecular Psychiatry,23(1), 59–69. https://doi.

org/10.1038/mp.2017.190

Kolp, E., Young, M. S., Friedman, H., Krupitsky, E., Jansen,

K., & O’Connor, L.-A. (2007). Ketamine-enhanced psy-

chotherapy: Preliminary clinical observations on its

effects in treating death anxiety. International Journal of

Transpersonal Studies,26(1), 1–17. https://doi.org/10.

24972/ijts.2007.26.1.1

Kraus, C., Wasserman, D., Henter, I. D., Acevedo-Diaz, E.,

Kadriu, B., & Zarate, C. A. (2019). The influence of keta-

mine on drug discovery in depression. Drug Discovery

Today,24(10), 2033–2043. https://doi.org/10.1016/j.dru-

dis.2019.07.007

Krupitsky, E. M., & Grinenko, A. Y. (1997). Ketamine psy-

chedelic therapy (KPT): A review of the results of ten

years of research. Journal of Psychoactive Drugs,29(2),

165–183. https://doi.org/10.1080/02791072.1997.10400185

Kryst, J., Kawalec, P., & Pilc, A. (2020). Efficacy and safety

of intranasal esketamine for the treatment of major

depressive disorder. Expert Opinion on Pharmacotherapy,

21(1), 9–20. https://doi.org/10.1080/14656566.2019.

1683161

Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S.,

& Duman, R. S. (2019). Ketamine: A paradigm shift for

depression research and treatment. Neuron,101(5),

774–778. https://doi.org/10.1016/j.neuron.2019.02.005

Kurdi, M. S., Theerth, K. A., & Deva, R. S. (2014).

Ketamine: Current applications in anesthesia, pain, and

critical care. Anesthesia, Essays and Researches,8(3),

283–290. https://doi.org/10.4103/0259-1162.143110

Laje, G., Lally, N., Mathews, D., Brutsche, N., Chemerinski,

A., Akula, N., Kelmendi, B., Simen, A., McMahon, F. J.,

Sanacora, G., & Zarate, C. (2012). Brain-derived neuro-

trophic factor Val66Met polymorphism and antidepres-

sant efficacy of ketamine in depressed patients. Biological

Psychiatry,72(11), e27–e28. https://doi.org/10.1016/j.

biopsych.2012.05.031

Lapidus, K. A. B., Levitch, C. F., Perez, A. M., Brallier,

J. W., Parides, M. K., Soleimani, L., Feder, A., Iosifescu,

D. V., Charney, D. S., & Murrough, J. W. (2014). A

randomized controlled trial of intranasal ketamine in

major depressive disorder. Biological Psychiatry,76(12),

970–976. https://doi.org/10.1016/j.biopsych.2014.03.026

Leal, G. C., Bandeira, I. D., & Correia-Melo, F. S. (2020).

Intravenous arketamine for treatment-resistant depres-

sion: Open-label pilot study. European Archives of

Psychiatry and Clinical Neuroscience. Advance online

publication. https://doi.org/10.1007/s00406-020-01110-5

Lener, M. S., Niciu, M. J., Ballard, E. D., Park, M., Park,

L. T., Nugent, A. C., & Zarate, C. A. (2017). Glutamate

and gamma-aminobutyric acid systems in the patho-

physiology of major depression and antidepressant

response to ketamine. Biological Psychiatry,81(10),

886–897. https://doi.org/10.1016/j.biopsych.2016.05.005

Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata,

M., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2010).

mTOR-dependent synapse formation underlies the rapid

antidepressant effects of NMDA antagonists. Science,

329(5994), 959–964. https://doi.org/10.1126/science.

1190287

Li, N., Liu, R.-J., Dwyer, J. M., Banasr, M., Lee, B., Son, H.,

Li, X.-Y., Aghajanian, G., & Duman, R. S. (2011).

Glutamate N-methyl-D-aspartate receptor antagonists

rapidly reverse behavioral and synaptic deficits caused by

chronic stress exposure. Biological Psychiatry,69(8),

754–761. https://doi.org/10.1016/j.biopsych.2010.12.015

Liu, R.-J., Fuchikami, M., Dwyer, J. M., Lepack, A. E.,

Duman, R. S., & Aghajanian, G. K. (2013). GSK-3 inhib-

ition potentiates the synaptogenic and antidepressant-like

effects of subthreshold doses of ketamine.

Neuropsychopharmacology,38(11), 2268–2277. https://doi.

org/10.1038/npp.2013.128

18 L. A. JELEN AND J. M. STONE

Loo, C. K., G

alvez, V., O’Keefe, E., Mitchell, P. B., Hadzi-

Pavlovic, D., Leyden, J., Harper, S., Somogyi, A. A., Lai,

R., Weickert, C. S., & Glue, P. (2016). Placebo-controlled

pilot trial testing dose titration and intravenous, intra-

muscular and subcutaneous routes for ketamine in

depression. Acta Psychiatrica Scandinavica,134(1),

48–56. https://doi.org/10.1111/acps.12572

Maeng, S., Zarate, C. A., Du, J., Schloesser, R. J.,

McCammon, J., Chen, G., & Manji, H. K. (2008).

Cellular mechanisms underlying the antidepressant

effects of ketamine: Role of alpha-amino-3-hydroxy-5-

methylisoxazole-4-propionic acid receptors. Biological

Psychiatry,63(4), 349–352. https://doi.org/10.1016/j.biop-

sych.2007.05.028

Malinow, R., & Klein, M. E. (2020). Reply to Hashimoto:

Ketamine is not an opioid but requires opioid system for

antidepressant actions. Proceedings of the National

Academy of Sciences of the United States of America,

117(21), 11202–11203. https://doi.org/10.1073/pnas.

2002739117

McShane, R. (2019). A drug not a miracle—Why we need a

new system for monitoring ketamine. BMJ. https://blogs.

bmj.com/bmj/2019/07/26/rupert-mcshane-a-drug-not-a-

miracle-why-we-need-a-new-system-for-monitoring-

ketamine/

Mendoza, M. C., Er. E. E. & Blenis, J. (2011). The Ras-ERK

and PI3K-mTOR pathways: cross-talk and compensation.

Trends in biochemical sciences, 36(6), 320–328.

Milak, M. S., Proper, C. J., Mulhern, S. T., Parter, A. L.,

Kegeles, L. S., Ogden, R. T., Mao, X., Rodriguez, C. I.,

Oquendo, M. A., Suckow, R. F., Cooper, T. B., Keilp,

J. G., Shungu, D. C., & Mann, J. J. (2016). A pilot

in vivo proton magnetic resonance spectroscopy study of

amino acid neurotransmitter response to ketamine treat-

ment of major depressive disorder. Molecular Psychiatry,

21(3), 320–327. https://doi.org/10.1038/mp.2015.83

Moghaddam, B., Adams, B., Verma, A., & Daly, D. (1997).

Activation of glutamatergic neurotransmission by keta-

mine: A novel step in the pathway from NMDA receptor

blockade to dopaminergic and cognitive disruptions asso-

ciated with the prefrontal cortex. The Journal of

Neuroscience,17(8), 2921–2927. https://doi.org/10.1523/

JNEUROSCI.17-08-02921.1997

Monteggia, L. M., Gideons, E., & Kavalali, E. T. (2013). The

role of eukaryotic elongation factor 2 kinase in rapid

antidepressant action of ketamine. Biological Psychiatry,

73(12), 1199–1203. https://doi.org/10.1016/j.biopsych.

2012.09.006

Morgan, C. J., & Curran, H. V. (2006). Acute and chronic

effects of ketamine upon human memory: A review.

Psychopharmacology,188(4), 408–424. https://doi.org/10.

1007/s00213-006-0572-3

Morgan, C. J., & Curran, H. V. (2012). Ketamine use: A

review. Addiction,107(1), 27–38. https://doi.org/10.1111/

j.1360-0443.2011.03576.x

Muller, J., Pentyala, S., Dilger, J., & Pentyala, S. (2016).

Ketamine enantiomers in the rapid and sustained anti-

depressant effects. Therapeutic Advances in

Psychopharmacology,6(3), 185–192. https://doi.org/10.

1177/2045125316631267

Murrough, J. W., Burdick, K. E., Levitch, C. F., Perez,

A. M., Brallier, J. W., Chang, L. C., Foulkes, A., Charney,

D. S., Mathew, S. J., & Iosifescu, D. V. (2015).

Neurocognitive effects of ketamine and association with

antidepressant response in individuals with treatment-

resistant depression: A randomized controlled trial.

Neuropsychopharmacology,40(5), 1084–1090. https://doi.

org/10.1038/npp.2014.298

Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi,

R. K., Green, C. E., Perez, A. M., Iqbal, S., Pillemer, S.,

Foulkes, A., Shah, A., Charney, D. S., & Mathew, S. J.

(2013). Antidepressant efficacy of ketamine in treatment-

resistant major depression: A two-site randomized con-

trolled trial. The American Journal of Psychiatry,170(10),

1134–1142. https://doi.org/10.1176/appi.ajp.2013.

13030392

Murrough, J. W., Soleimani, L., DeWilde, K. E., Collins,

K. A., Lapidus, K. A., Iacoviello, B. M., Lener, M., Kautz,

M., Kim, J., Stern, J. B., Price, R. B., Perez, A. M.,

Brallier, J. W., Rodriguez, G. J., Goodman, W. K.,

Iosifescu, D. V., & Charney, D. S. (2015). Ketamine for

rapid reduction of suicidal ideation: A randomized con-

trolled trial. Psychological Medicine,45(16), 3571–3580.

https://doi.org/10.1017/S0033291715001506

Niciu, M. J., Luckenbaugh, D. A., Ionescu, D. F., Guevara,

S., Machado-Vieira, R., Richards, E. M., Brutsche, N. E.,

Nolan, N. M., & Zarate, C. A. (2014). Clinical predictors

of ketamine response in treatment-resistant major

depression. The Journal of Clinical Psychiatry,75(05),

e417–e423. https://doi.org/10.4088/JCP.13m08698

Nugent, A. C., Ballard, E. D., Gould, T. D., Park, L. T.,

Moaddel, R., Brutsche, N. E., & Zarate, C. A. (2019).

Ketamine has distinct electrophysiological and behavioral

effects in depressed and healthy subjects. Molecular

Psychiatry,24(7), 1040–1052. https://doi.org/10.1038/

s41380-018-0028-2

Ochs-Ross, R., Daly, E. J., Zhang, Y., Lane, R., Lim, P.,

Morrison, R. L., Hough, D., Manji, H., Drevets, W. C.,

Sanacora, G., Steffens, D. C., Adler, C., McShane, R.,

Gaillard, R., Wilkinson, S. T., & Singh, J. B. (2020).

Efficacy and safety of esketamine nasal spray plus an oral

antidepressant in elderly patients with treatment-resistant

depression-TRANSFORM-3. The American Journal of

Geriatric Psychiatry,28(2), 121–141. https://doi.org/10.

1016/j.jagp.2019.10.008

Peltoniemi, M. A., Hagelberg, N. M., Olkkola, K. T., &

Saari, T. I. (2016). Ketamine: A review of clinical

pharmacokinetics and pharmacodynamics in anesthesia

and pain therapy. Clinical Pharmacokinetics,55(9),

1059–1077. https://doi.org/10.1007/s40262-016-0383-6

Pham, T. H., Defaix, C., Xu, X., Deng, S.-X., Fabresse, N.,

Alvarez, J.-C., Landry, D. W., Brachman, R. A., Denny,

C. A., & Gardier, A. M. (2018). Common neurotransmis-

sion recruited in (R,S)-ketamine and (2R,6R)-hydroxy-

norketamine-induced sustained antidepressant-like

effects. Biological Psychiatry,84(1), e3–e6. https://doi.org/

10.1016/j.biopsych.2017.10.020

Pham, T. H., Mendez-David, I., Defaix, C., Guiard, B. P.,

Tritschler, L., David, D. J., & Gardier, A. M. (2017).

Ketamine treatment involves medial prefrontal cortex

serotonin to induce a rapid antidepressant-like activity in

BALB/cJ mice. Neuropharmacology,112(Pt A), 198–209.

https://doi.org/10.1016/j.neuropharm.2016.05.010

INTERNATIONAL REVIEW OF PSYCHIATRY 19

Popova, V., Daly, E. J., Trivedi, M., Cooper, K., Lane, R.,

Lim, P., Mazzucco, C., Hough, D., Thase, M. E., Shelton,

R. C., Molero, P., Vieta, E., Bajbouj, M., Manji, H.,

Drevets, W. C., & Singh, J. B. (2019). Efficacy and safety

of flexibly dosed esketamine nasal spray combined with a

newly initiated oral antidepressant in treatment-resistant

depression: A randomized double-blind active-controlled

study. The American Journal of Psychiatry,176(6),

428–438. https://doi.org/10.1176/appi.ajp.2019.19020172

Quevedo, K., Ng, R., Scott, H., Kodavaganti, S., Smyda, G.,

Diwadkar, V., & Phillips, M. (2017). Ventral striatum

functional connectivity during rewards and losses and

symptomatology in depressed patients. Biological

Psychology,123,62–73. https://doi.org/10.1016/j.biopsy-

cho.2016.11.004

Riva-Posse, P., Reiff, C. M., Edwards, J. A., Job, G. P.,

Galendez, G. C., Garlow, S. J., Saah, T. C., Dunlop,

B. W., & McDonald, W. M. (2018). Blood pressure safety

of subanesthetic ketamine for depression: A report on

684 infusions. Journal of Affective Disorders,236,

291–297. https://doi.org/10.1016/j.jad.2018.02.025

Rodriguez-Munoz, M., Sanchez-Blazquez, P., & Vicente-

Sanchez, A. (2012). The mu-opioid receptor and the

NMDA receptor associate in PAG neurons: Implications

in pain control. Neuropsychopharmacology,37(2),

338–349. https://doi.org/10.1038/npp.2011.155

Rong, C., Park, C., & Rosenblat, J. D. (2018). Predictors of

response to ketamine in treatment resistant major

depressive disorder and bipolar disorder. International

Journal of Environmental Research and Public Health,

15(4), 771. https://doi.org/10.3390/ijerph15040771

Salvadore, G., Cornwell, B. R., Colon-Rosario, V., Coppola,

R., Grillon, C., Zarate, C. A., & Manji, H. K. (2009).

Increased anterior cingulate cortical activity in response

to fearful faces: A neurophysiological biomarker that pre-

dicts rapid antidepressant response to ketamine.

Biological Psychiatry,65(4), 289–295. https://doi.org/10.

1016/j.biopsych.2008.08.014

Salvadore, G., van der Veen, J. W., Zhang, Y., Marenco, S.,

Machado-Vieira, R., Baumann, J., Ibrahim, L. A.,

Luckenbaugh, D. A., Shen, J., Drevets, W. C., & Zarate,

C. A. (2012). An investigation of amino-acid neurotrans-

mitters as potential predictors of clinical improvement to

ketamine in depression. The International Journal of

Neuropsychopharmacology,15(08), 1063–1072. https://doi.

org/10.1017/S1461145711001593

Sassano-Higgins, S., Baron, D., Juarez, G., Esmaili, N., &

Gold, M. (2016). A review of ketamine abuse and diver-

sion. Depression and Anxiety,33(8), 718–727. https://doi.

org/10.1002/da.22536

Schatzberg, A. F. (2014). A word to the wise about keta-

mine. The American Journal of Psychiatry,171(3),

262–264. https://doi.org/10.1176/appi.ajp.2014.13101434

Shahani, R., Streutker, C., Dickson, B., & Stewart, R. J.

(2007). Ketamine-associated ulcerative cystitis: A new

clinical entity. Urology,69(5), 810–812. https://doi.org/10.

1016/j.urology.2007.01.038

Shirayama, Y., & Hashimoto, K. (2018). Lack of antidepres-

sant effects of (2R,6R)-hydroxynorketamine in a rat

learned helplessness model: Comparison with (R)-keta-

mine. The International Journal of

Neuropsychopharmacology,21(1), 84–88. https://doi.org/

10.1093/ijnp/pyx108

Short, B., Fong, J., Galvez, V., Shelker, W., & Loo, C. K.

(2018). Side-effects associated with ketamine use in

depression: A systematic review. The Lancet. Psychiatry,

5(1), 65–78. https://doi.org/10.1016/S2215-

0366(17)30272-9

Singh, J. B., Fedgchin, M., Daly, E., Xi, L., Melman, C., De

Bruecker, G., Tadic, A., Sienaert, P., Wiegand, F., Manji,

H., Drevets, W. C., & Van Nueten, L. (2016).

Intravenous esketamine in adult treatment-resistant

depression: A double-blind, double-randomization, pla-

cebo-controlled study. Biological Psychiatry,80(6),

424–431. https://doi.org/10.1016/j.biopsych.2015.10.018

Singh, J. B., Fedgchin, M., Daly, E. J., De Boer, P., Cooper,

K., Lim, P., Pinter, C., Murrough, J. W., Sanacora, G.,

Shelton, R. C., Kurian, B., Winokur, A., Fava, M., Manji,

H., Drevets, W. C., & Van Nueten, L. (2016). A double-

blind, randomized, placebo-controlled, dose-frequency

study of intravenous ketamine in patients with treat-

ment-resistant depression. The American Journal of

Psychiatry,173(8), 816–826. https://doi.org/10.1176/appi.

ajp.2016.16010037

Smith, G. S., Schloesser, R., Brodie, J. D., Dewey, S. L.,

Logan, J., Vitkun, S. A., Simkowitz, P., Hurley, A.,

Cooper, T., Volkow, N. D., & Cancro, R. (1998).

Glutamate modulation of dopamine measured in vivo

with positron emission tomography (PET) and 11C-

raclopride in normal human subjects.

Neuropsychopharmacology,18(1), 18–25. https://doi.org/

10.1016/S0893-133X(97)00092-4

Sos, P., Klirova, M., Novak, T., Kohutova, B., Horacek, J., &

Palenicek, T. (2013). Relationship of ketamine’s anti-

depressant and psychotomimetic effects in unipolar

depression. Neuro Endocrinology Letters,34(4), 287–293.

Sterpenich, V., Vidal, S., Hofmeister, J., Michalopoulos, G.,

Bancila, V., Warrot, D., Dayer, A., Desseilles, M., Aubry,

J.-M., Kosel, M., Schwartz, S., & Vutskits, L. (2019).

Increased reactivity of the mesolimbic reward system

after ketamine injection in patients with treatment-resist-

ant major depressive disorder. Anesthesiology,130(6),

923–935. https://doi.org/10.1097/ALN.0000000000002667

Su, T.-P., Chen, M.-H., Li, C.-T., Lin, W.-C., Hong, C.-J.,

Gueorguieva, R., Tu, P.-C., Bai, Y.-M., Cheng, C.-M., &

Krystal, J. H. (2017). Dose-related effects of adjunctive

ketamine in taiwanese patients with treatment-resistant

depression. Neuropsychopharmacology,42(13),

2482–2492. https://doi.org/10.1038/npp.2017.94

Swainson, J., Thomas, R. K., Archer, S., Chrenek, C.,

MacKay, M.-A., Baker, G., Dursun, S., Klassen, L. J.,

Chokka, P., & Demas, M. L. (2019). Esketamine for treat-

ment resistant depression. Expert Review of

Neurotherapeutics,19(10), 899–911. https://doi.org/10.

1080/14737175.2019.1640604

Turner, E. H. (2019). Esketamine for treatment-resistant

depression: Seven concerns about efficacy and FDA

approval. The Lancet. Psychiatry,6(12), 977–979. https://

doi.org/10.1016/S2215-0366(19)30394-3

Vollenweider, F. X., Leenders, K. L., Oye, I., Hell, D., &

Angst, J. (1997). Differential psychopathology and pat-

terns of cerebral glucose utilisation produced by (S)- and

(R)-ketamine in healthy volunteers using positron

20 L. A. JELEN AND J. M. STONE

emission tomography (PET). European

Neuropsychopharmacology: The Journal of the European

College of Neuropsychopharmacology,7(1), 25–38. https://

doi.org/10.1016/s0924-977x(96)00042-9

Vollenweider, F. X., Vontobel, P., Øye, I., Hell, D., &

Leenders, K. L. (2000). Effects of (S)-ketamine on striatal

dopamine: A [11C]raclopride PET study of a model

psychosis in humans. Journal of Psychiatric Research,

34(1), 35–43. https://doi.org/10.1016/S0022-

3956(99)00031-X

Wan, L.-B., Levitch, C. F., Perez, A. M., Brallier, J. W.,

Iosifescu, D. V., Chang, L. C., Foulkes, A., Mathew, S. J.,

Charney, D. S., & Murrough, J. W. (2015). Ketamine

safety and tolerability in clinical trials for treatment-

resistant depression. The Journal of Clinical Psychiatry,

76(03), 247–252. https://doi.org/10.4088/JCP.13m08852

White, P. F., Ham, J., Way, W. L., & Trevor, A. J. (1980).

Pharmacology of ketamine isomers in surgical patients.

Anesthesiology,52(3), 231–239. https://doi.org/10.1097/

00000542-198003000-00008

White, P. F., Sch€

uttler, J., Shafer, A., Stanski, D. R., Horai,

Y., & Trevor, A. J. (1985). Comparative pharmacology of

the ketamine isomers. Studies in volunteers. British

Journal of Anaesthesia,57(2), 197–203. https://doi.org/10.

1093/bja/57.2.197

WHO. (2017). Depression and other common mental disor-

ders: Global health estimates. World Health Organization.

Widman, A. J., & McMahon, L. L. (2018). Disinhibition of

CA1 pyramidal cells by low-dose ketamine and other

antagonists with rapid antidepressant efficacy.

Proceedings of the National Academy of Sciences of the

United States of America,115(13), E3007–E3016. https://

doi.org/10.1073/pnas.1718883115

Wilkinson, S. T., Ballard, E. D., Bloch, M. H., Mathew,

S. J., Murrough, J. W., Feder, A., Sos, P., Wang, G.,

Zarate, C. A., & Sanacora, G. (2018). The effect of a sin-

gle dose of intravenous ketamine on suicidal ideation: A

systematic review and individual participant data meta-

analysis. The American Journal of Psychiatry,175(2),

150–158. https://doi.org/10.1176/appi.ajp.2017.17040472

Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K.,

Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons,

D. M., Rodriguez, C. I., & Schatzberg, A. F. (2018).

Attenuation of antidepressant effects of ketamine by opi-

oid receptor antagonism. The American Journal of

Psychiatry,175(12), 1205–1215. https://doi.org/10.1176/

appi.ajp.2018.18020138

Winstock, A. R., Mitcheson, L., Gillatt, D. A., & Cottrell,

A. M. (2012). The prevalence and natural history of urin-

ary symptoms among recreational ketamine users. BJU

International,110(11), 1762–1766. https://doi.org/10.

1111/j.1464-410X.2012.11028.x

Xu, A. J., Niciu, M. J., Lundin, N. B., Luckenbaugh, D. A.,

Ionescu, D. F., Richards, E. M., Vande Voort, J. L.,

Ballard, E. D., Brutsche, N. E., Machado-Vieira, R., &

Zarate, C. A. (2015). Lithium and valproate levels do not

correlate with ketamine’s antidepressant efficacy in treat-

ment-resistant bipolar depression. Neural Plasticity,2015,

1–7. https://doi.org/10.1155/2015/858251

Yamaguchi, J.-I., Toki, H., Qu, Y., Yang, C., Koike, H.,

Hashimoto, K., Mizuno-Yasuhira, A., & Chaki, S. (2018).

(2R,6R)-Hydroxynorketamine is not essential for the

antidepressant actions of (R)-ketamine in mice.

Neuropsychopharmacology,43(9), 1900–1907. https://doi.

org/10.1038/s41386-018-0084-y

Yang, C., Kobayashi, S., Nakao, K., Dong, C., Han, M., Qu,

Y., Ren, Q., Zhang, J.-C., Ma, M., Toki, H., Yamaguchi,

J.-I., Chaki, S., Shirayama, Y., Nakazawa, K., Manabe, T.,

& Hashimoto, K. (2018). AMPA receptor activation-inde-

pendent antidepressant actions of ketamine metabolite

(S)-norketamine. Biological Psychiatry,84(8), 591–600.

https://doi.org/10.1016/j.biopsych.2018.05.007

Yang, C., Qu, Y., Abe, M., Nozawa, D., Chaki, S., &

Hashimoto, K. (2017). (R)-ketamine shows greater

potency and longer lasting antidepressant effects than its

metabolite (2R,6R)-hydroxynorketamine. Biological

Psychiatry,82(5), e43–e44. https://doi.org/10.1016/j.biop-

sych.2016.12.020

Yang, C., Ren, Q., Qu, Y., Zhang, J.-C., Ma, M., Dong, C.,

& Hashimoto, K. (2018). Mechanistic target of rapamy-

cin-independent antidepressant effects of (R)-ketamine in

a social defeat stress model. Biological Psychiatry,83(1),

18–28. https://doi.org/10.1016/j.biopsych.2017.05.016

Yang, C., Shirayama, Y., Zhang, J-c., Ren, Q., Yao, W., Ma,

M., Dong, C., & Hashimoto, K. (2015). R-ketamine: A

rapid-onset and sustained antidepressant without psych-

otomimetic side effects. Translational Psychiatry,5, e632.

https://doi.org/10.1038/tp.2015.136

Yang, C., Wardenaar, K. J., Bosker, F. J., Li, J., & Schoevers,

R. A. (2019). Inflammatory markers and treatment out-

come in treatment resistant depression: A systematic

review. Journal of Affective Disorders,257, 640–649.

https://doi.org/10.1016/j.jad.2019.07.045

Yang, C., Yang, J., Luo, A., & Hashimoto, K. (2019).

Molecular and cellular mechanisms underlying the anti-

depressant effects of ketamine enantiomers and its

metabolites. Translational Psychiatry,9(1), 280. https://

doi.org/10.1038/s41398-019-0624-1

Yang, Y., Cui, Y., Sang, K., Dong, Y., Ni, Z., Ma, S., & Hu,

H. (2018). Ketamine blocks bursting in the lateral habe-

nula to rapidly relieve depression. Nature,554(7692),

317–322. https://doi.org/10.1038/nature25509

Yoon, G., Petrakis, I. L., & Krystal, J. H. (2019).

Association of combined naltrexone and ketamine with

depressive symptoms in a case series of patients with

depression and alcohol use disorder. JAMA Psychiatry,

76(3), 337–338. https://doi.org/10.1001/jamapsychiatry.

2018.3990

Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell,

J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J.,

Singh, N. S., Dossou, K. S. S., Fang, Y., Huang, X.-P.,

Mayo, C. L., Wainer, I. W., Albuquerque, E. X.,

Thompson, S. M., Thomas, C. J., Zarate, C. A., & Gould,

T. D. (2016). NMDAR inhibition-independent anti-

depressant actions of ketamine metabolites. Nature,

533(7604), 481–486. https://doi.org/10.1038/nature17998

Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M.,

Highland, J. N., Georgiou, P., Pereira, E. F. R.,

Albuquerque, E. X., Thomas, C. J., Zarate, C. A., &

Gould, T. D. (2018). Ketamine and ketamine metabolite

pharmacology: Insights into therapeutic mechanisms.

Pharmacological Reviews,70(3), 621–660. https://doi.org/

10.1124/pr.117.015198

INTERNATIONAL REVIEW OF PSYCHIATRY 21

Zarate, C. A., Brutsche, N., Laje, G., Luckenbaugh, D. A.,

Venkata, S. L. V., Ramamoorthy, A., Moaddel, R., &

Wainer, I. W. (2012). Relationship of ketamine’s plasma

metabolites with response, diagnosis, and side effects in

major depression. Biological Psychiatry,72(4), 331–338.

https://doi.org/10.1016/j.biopsych.2012.03.004

Zarate, C. A., Brutsche, N. E., Ibrahim, L., Franco-Chaves,

J., Diazgranados, N., Cravchik, A., Selter, J., Marquardt,

C. A., Liberty, V., & Luckenbaugh, D. A. (2012).

Replication of ketamine’s antidepressant efficacy in bipo-

lar depression: A randomized controlled add-on trial.

Biological Psychiatry,71(11), 939–946. https://doi.org/10.

1016/j.biopsych.2011.12.010

Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E.,

Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji,

H. K. (2006). A randomized trial of an N-methyl-D-

aspartate antagonist in treatment-resistant major

depression. Archives of General Psychiatry,63(8),

856–864. https://doi.org/10.1001/archpsyc.63.8.856

Zhang, K., & Hashimoto, K. (2019). Lack of opioid system

in the antidepressant actions of ketamine. Biological

Psychiatry,85(6), e25–e27. https://doi.org/10.1016/j.biop-

sych.2018.11.006

Zhao, Y., & Sun, L. (2008). Antidepressants modulate the

in vitro inhibitory effects of propofol and ketamine on

norepinephrine and serotonin transporter function.

Journal of Clinical Neuroscience,15(11), 1264–1269.

https://doi.org/10.1016/j.jocn.2007.11.007

Zhou, W., Wang, N., Yang, C., Li, X.-M., Zhou, Z.-Q., &

Yang, J.-J. (2014). Ketamine-induced antidepressant

effects are associated with AMPA receptors-mediated

upregulation of mTOR and BDNF in rat hippocampus

and prefrontal cortex. European Psychiatry: The Journal

of the Association of European Psychiatrists,29(7),

419–423. https://doi.org/10.1016/j.eurpsy.2013.10.005

22 L. A. JELEN AND J. M. STONE

Ketamine Infusion for Complex Regional Pain Syndrome Treatment: A Narrative Review

Article

Full-text available

Jan 2025
Curr Pain Headache Rep

Purpose of Review Complex Regional Pain Syndrome (CRPS) is a neuropathic pain disorder characterized by pain disproportionate to the inciting event that is constant for an extended duration. Numerous treatment options for this condition have been explored with unsatisfactory results in many cases. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist typically used as an anesthetic and analgesic, presents a promising potential treatment for CRPS in patients who fail to respond to traditional therapies. Recent Findings Numerous studies report significant improvement in the degree of pain, mobility of extremities, and other parameters after ketamine infusion in patients with CRPS. Although adverse effects were not reported often, some subjects experienced nausea, vomiting, headache or psychotropic or psychomimetic symptoms which could be mitigated with cessation of the drug. Although more research is needed to determine optimal dosing and duration, ketamine seems to be a safe and effective treatment for refractory cases of CRPS. Conclusion The present investigation summarizes existing knowledge and research surrounding ketamine infusions for CRPS to provide a well-rounded depiction of advantages and disadvantages for physicians who may be considering it for patients with this challenging and complex condition.

Ketamine and the Consequences of Positive Psychedelic Exceptionalism

Article

Jan 2025
AM J BIOETHICS

Optogenetics and chemogenetics: key tools for modulating neural circuits in rodent models of depression

Article

Full-text available

Feb 2025

Optogenetics and chemogenetics are emerging neuromodulation techniques that have attracted significant attention in recent years. These techniques enable the precise control of specific neuronal types and neural circuits, allowing researchers to investigate the cellular mechanisms underlying depression. The advancement in these techniques has significantly contributed to the understanding of the neural circuits involved in depression; when combined with other emerging technologies, they provide novel therapeutic targets and diagnostic tools for the clinical treatment of depression. Additionally, these techniques have provided theoretical support for the development of novel antidepressants. This review primarily focuses on the application of optogenetics and chemogenetics in several brain regions closely associated with depressive-like behaviors in rodent models, such as the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, dorsal raphe nucleus, and lateral habenula and discusses the potential and challenges of optogenetics and chemogenetics in future research. Furthermore, this review discusses the potential and challenges these techniques pose for future research and describes the current state of research on sonogenetics and odourgenetics developed based on optogenetics and chemogenetics. Specifically, this study aimed to provide reliable insights and directions for future research on the role of optogenetics and chemogenetics in the neural circuits of depressive rodent models.

Brain-derived neurotrophic factor (BDNF) changes in rodent models of schizophrenia induced by ketamine: a systematic review

Article

Full-text available

Feb 2025
N Schmied Arch Pharmacol

Schizophrenia is a severe neuropsychiatric disorder ranking among the top ten global disability causes. In rodents, sub-chronic or chronic ketamine treatment is used for the induction of schizophrenia. Ketamine affects the function of brain-derived neurotrophic factor (BDNF), the most important neurotrophin involved in the pathophysiology of different neuropsychiatric disorders. The present systematic review aimed to investigate BDNF changes in rodent studies used ketamine-induced schizophrenia. PubMed electronic database was searched and 44 articles were found. After removal of unrelated articles, 17 articles were selected. The results showed a wide range of inconsistent changes in BDNF levels. We found that sub-chronic and chronic ketamine treatment in rats decreased BDNF or had no effect. Sub-chronic and chronic ketamine treatment in mice only decreased BDNF. However, increased BDNF was commonly observed following acute ketamine treatment. These results showed the possible role of species and the duration of treatment. Also, sex can also be involved in BDNF changes because one study showed inconsistent BDNF changes in male and female rats. In conclusion, we found that ketamine's effects may depend on factors such as duration of administration, sex, and species. Therefore, the wide range of BDNF changes may be related to high variability in methods. Because of this variability, there is currently no standardized method for using ketamine as a rodent model for schizophrenia. Further research is needed to establish a standardized pharmacological model of schizophrenia using ketamine treatment.

Esketamine reduces postoperative depression in breast cancer through TREK-1 channel inhibition and neurotransmitter modulation

Article

Full-text available

Feb 2025
Canc Cell Int

Postoperative depression significantly affects the quality of life of breast cancer patients. This study explores the potential therapeutic effects of esketamine on postoperative depression through modulation of the TREK-1 two-pore domain potassium channel. We analyzed data from 54 female breast cancer patients who underwent surgery at our hospital between 2019 and 2023, dividing them into experimental and control groups based on esketamine treatment. Transcriptomic sequencing of hippocampal neurons from rats identified potassium ion-related pathways and key regulatory genes, including TREK-1, influenced by esketamine. In vitro studies showed that esketamine primarily alleviates depressive symptoms by inhibiting TREK-1 protein expression, enhancing GABA neurotransmitter release, and improving neuronal activity, while overexpression of TREK-1 reversed these effects. Esketamine’s inhibition of TREK-1 channels and promotion of hippocampal neuron activity effectively alleviate postoperative depression in breast cancer patients, suggesting a novel therapeutic strategy. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-025-03664-7.

The Role of Ketamine in Treatment-resistant Depression: A Narrative Review

Article

Full-text available

Dec 2024

Ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, has emerged as an effective therapeutic agent for the management of treatment-resistant depression. Repeated treatments with ketamine show rapid, robust, and sustained antidepressant effects. Despite the large body of evidence, key concerns include adverse effects such as dissociative symptoms, hemodynamic instability, and the risk of abuse with long-term ketamine therapy. This narrative review provides an overview of the neurobiological mechanisms underlying ketamine’s antidepressant effects, its basic pharmacodynamics, and its safety profile. The clinical evidence regarding ketamine’s efficacy in depression is also summarized, and the need for further research on the long-term effects of ketamine therapy, the development of agents with similar antidepressant effects but fewer adverse effects or potential for abuse, and the identification of biomarkers to predict the response to ketamine is highlighted.

Mechanisms of NMDA receptor inhibition by vortioxetine – Comparison with fluoxetine

Article

Mar 2025
EUR J PHARMACOL

A pilot study of ketamine among individuals with tobacco use disorder: tolerability and initial impact on tobacco use outcomes

Article

Jan 2025
J ADDICT DIS

Is there a risk of addiction to ketamine during the treatment of depression? A systematic review of available literature

Article

Dec 2024

Background Ketamine has demonstrated both rapid and sustained efficacy in treating depression, especially in treatment-resistant cases. However, concerns regarding the addictive potential of ketamine during long-term depression treatment persist among clinicians. Aim This review aimed to summarise the evidence on addiction phenomena associated with ketamine treatment of depression. Methods A comprehensive search was conducted in MEDLINE, Embase, PsycInfo and Global Health databases, with additional relevant studies identified through reference lists. Sixteen studies were included, comprising six randomised controlled trials, three single-arm open-label studies, one retrospective study, three case series and three case reports, for a total of 2174 patients. Results The studies employed various routes of administration, including intravenous, intramuscular, intranasal, oral and sublingual. Ketamine was administered in the racemic form, except for the studies that utilised intranasal esketamine. Among the included population, four patients were reported to exhibit clear signs of tolerance to the antidepressant effect of ketamine or dependence on the drug, while the majority did not. Cases of addiction phenomena reported in studies that did not meet the inclusion criteria are also discussed. Conclusions Despite the heterogeneity in study designs and outcome assessment methods, the review underscores the relative safety of ketamine treatment for adult patients with depression, emphasising the importance of medically supervised administration, vigilant monitoring and judicious dosing. Future long-term studies employing quantitative scales to assess dependence phenomena could contribute to strengthening the evidence for the safe and effective use of ketamine in the treatment of depression.

Pharmacotherapeutic strategies for the treatment of anorexia nervosa - novel targets to break a vicious cycle

Article

Nov 2024
EXPERT OPIN PHARMACO

Introduction: Anorexia nervosa (AN) has one of the highest mortality rates of all mental illnesses. No approved pharmacological treatments exist for AN, but novel neurobiological targets show promise. Areas covered: Studies show that in individuals with AN, there are alterations in brain neurotransmitter signaling, alongside associated mental rigidity and comorbid anxiety and depression. Available and new therapies could be used to improve alterations in neurobiology and behavior. This narrative review serves as a review of previously published literature assessing the efficacy of traditional pharmacotherapy in treating AN while also exploring novel treatments, including dissociative anesthetics, psychedelics, cannabinoids, hormones, neurosteroids, and ketogenic nutrition. Expert opinion: If best practice psychotherapeutic interventions have failed, we recommend a neuroscience and brain research-based medication approach that targets dopamine neurotransmitter receptors to enhance cognitive flexibility and illness insight while reducing dread and avoidance toward food. It is furthermore essential to recognize and treat comorbid conditions such as anxiety, depression, or obsessive-compulsive disorder as they interfere with recovery, and typically do not resolve even with successful AN treatment. Novel strategies have the promise to show efficacy in improving mood and reducing specific AN psychopathology with hopes to be used in clinical practice soon.

Ketamine: A tale of two enantiomers

Article

Full-text available

Nov 2020

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine

Article

Full-text available

Mar 2020
BIOCHEM PHARMACOL

Kenji Hashimoto

Ketamine, an anesthetic developed in the early 1960s, is also a popular abused drug among young people at dance parties and raves and among spiritual seekers, because it produces schizophrenia-like symptoms and dissociation (i.e., out-of-body experience). Regarding mood disorders, ketamine exerts robust antidepressant actions in treatment-resistant patients with depression. Ketamine is a racemic mixture comprising equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). The United States (US) Food and Drug Administration approved the J&J (S)-ketamine nasal spray for treatment-resistant depression on March 5, 2019; the spray was then approved in Europe (December 19, 2019). Although (R)-ketamine has lower affinity for the N-methyl-d-aspartate receptor (NMDAR) vs. (S)-ketamine, (R)-ketamine has greater potency and longer-lasting antidepressant-like actions in animal models of depression. Importantly, (R)-ketamine has less detrimental side effects than does (R,S)-ketamine or (S)-ketamine in rodents, monkeys, and humans. A role for the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) receptor in the antidepressant effects of ketamine and its two enantiomers has been suggested. A recent RNA-sequencing analysis suggested that the transforming growth factor β1 (TGF-β1) plays a role in the antidepressant effects of (R)-ketamine. A recent pilot study demonstrated that (R)-ketamine had rapid-acting and sustained antidepressant effects in treatment-resistant patients with depression. In this article, the author reviews the mechanisms of the antidepressant actions of the enantiomers of ketamine and its metabolites, (S)-norketamine and (2R,6R)-hydroxynorketamine (HNK) and discusses the role of the brain–gut–microbiota axis and brain–spleen axis in stress-related psychiatric disorders, such as depression.

Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents

Article

Full-text available

Jan 2020

Significance Ketamine, an NMDA receptor antagonist, has generated intense excitement as a therapy for treatment-resistant depression. However, ketamine and its metabolites can act on a wide range of targets, including opioid receptors, which has raised concerns. Using behavioral and cellular assays in rodents, we find that blocking opioid function prevents the antidepressant-like effects of ketamine. However, in contrast to ketamine, administration of a µ-opioid agonist is hedonic and ineffective on anhedonia/avolition. Furthermore, ketamine’s cellular actions are both mimicked and occluded by an NMDAR antagonist but not by a µ-opioid agonist. These results suggest that ketamine does not act as a μ-opioid agonist, but functional μ-opioid receptors are permissive for the antidepressant effects of ketamine.

GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions

Article

Full-text available

Nov 2019
J CLIN INVEST

A single sub-anesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates these and its behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrate that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst), or parvalbumin (Pvalb), but not glutamate principle neurons in the mPFC. Further analysis of GABA subtypes showed that cell specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.

Comprehensive Assessment of Side Effects Associated with a Single Dose of Ketamine in Treatment-Resistant Depression

Article

Full-text available

Nov 2019
J AFFECT DISORDERS

Background: Concerns about ketamine for treating depression include abuse potential and the occurrence of psychotomimetic effects. This study sought to comprehensively assess side effects (SEs) associated with a single subanesthetic-dose intravenous ketamine infusion. A secondary aim was to examine the relationship between Clinician-Administered Dissociative States Scale (CADSS) scores and dissociative symptoms reported on a comprehensive, clinician-administered SE questionnaire. Methods: Data from 188 participants were pooled from four placebo-controlled, crossover ketamine trials and one open-label study (n = 163 with either treatment-resistant major depressive disorder or bipolar disorder and 25 healthy controls). SEs were actively solicited in a standardized fashion and monitored over the time-course of each study. Statistical analyses assessed the effect of drug (ketamine, placebo) on SEs and measured the relationship between CADSS total score and SEs contemporaneously endorsed during structured interviews. Results: Forty-four of 120 SEs occurred in at least 5% of participants over all trials. Thirty-three of these 44 SEs were significantly associated with active drug administration (versus placebo). The most common SE was feeling strange/weird/loopy. Most SEs peaked within an hour of ketamine administration and resolved completely by two hours post-infusion. No serious drug-related adverse events or increased ketamine craving/abuse post-administration were observed. A positive correlation was found between dissociative SEs and total CADSS score. Limitations: The post-hoc nature of the analysis; the limited generalizability of a single subanesthetic-dose ketamine infusion; and the lack of formal measures to assess ketamine's cognitive, urological, or addictive potential. Conclusions: No long-lasting significant SEs occurred over the approximately three-month follow-up period.

Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites

Article

Full-text available

Nov 2019

Although the robust antidepressant effects of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine in patients with treatment-resistant depression are beyond doubt, the precise molecular and cellular mechanisms underlying its antidepressant effects remain unknown. NMDAR inhibition and the subsequent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation are suggested to play a role in the antidepressant effects of ketamine. Although (R)-ketamine is a less potent NMDAR antagonist than (S)-ketamine, (R)-ketamine has shown more marked and longer-lasting antidepressant-like effects than (S)-ketamine in several animal models of depression. Furthermore, non-ketamine NMDAR antagonists do not exhibit robust ketamine-like antidepressant effects in patients with depression. These findings suggest that mechanisms other than NMDAR inhibition play a key role in the antidepressant effects of ketamine. Duman’s group demonstrated that the activation of mammalian target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex is reportedly involved in the antidepressant effects of ketamine. However, we reported that mTORC1 serves a role in the antidepressant effects of (S)-ketamine, but not of (R)-ketamine, and that extracellular signal-regulated kinase possibly underlie the antidepressant effects of (R)-ketamine. Several lines of evidence have demonstrated that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are crucial in the antidepressant effects of ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, in rodents. In addition, (2R,6R)-hydroxynormetamine [a metabolite of (R)-ketamine] and (S)-norketamine [a metabolite of (S)-ketamine] have been shown to exhibit antidepressant-like effects on rodents through the BDNF–TrkB cascade. In this review, we discuss recent findings on the molecular and cellular mechanisms underlying the antidepressant effects of enantiomers of ketamine and its metabolites. It may be time to reconsider the hypothesis of NMDAR inhibition and the subsequent AMPAR activation in the antidepressant effects of ketamine.

Reply to Hashimoto: Ketamine is not an opioid but requires opioid system for antidepressant actions

Article

May 2020

Intravenous arketamine for treatment-resistant depression: open-label pilot study

Article

Feb 2020

We aimed to analyze the efficacy and safety of arketamine, the R(−)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points [CI 95% 13.6–27.0; p < 0.001]; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.

Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval

Article

Nov 2019

Erick H Turner

Efficacy and safety of intranasal esketamine for the treatment of major depressive disorder

Article

Oct 2019

Introduction: In March 2019, intranasal esketamine was approved by the Food and Drug Administration (FDA) for the treatment of treatment-resistant depression (TRD) in adults. This review presents the results of clinical trials underlying the FDA approval of intranasal esketamine. Areas covered: Esketamine’s efficacy and safety in TRD were assessed in 5 phase III studies: three 4-week, placebo-controlled studies, and two long-term trials. One short-term trial showed statistically significant antidepressant effects of esketamine vs placebo, while a long-term withdrawal study showed that esketamine is significantly beneficial in terms of extending time to relapse, compared to placebo. Two other short-term trials did not meet the prespecified statistical tests for showing efficacy, although improvement in depressive symptoms from baseline to the end of week 4 favors esketamine over placebo. Expert opinion: Intranasal esketamine is a new treatment option for people with TRD. The main benefit of esketamine is rapid onset of antidepressant activity, but the effects of prolonged treatment are still preliminary. The main concerns relate to the safety aspects of prolonged esketamine therapy, when considering its abuse potential. While data for esketamine use over a long period of time is lacking, its use should be carefully monitored.