Side-effects associated with ketamine use in depression: a systematic review

www.thelancet.com/psychiatry Vol 5 January 2018

Review

Side-eﬀects associated with ketamine use in depression:

a systematic review

Brooke Short, Joanna Fong, Veronica Galvez, William Shelker, Colleen K Loo

This is the ﬁrst systematic review of the safety of ketamine in the treatment of depression after single and repeated

doses. We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identiﬁed 288 articles, 60 of which

met the inclusion criteria. After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other

side-eects were more frequently reported after ketamine treatment than after placebo in patients with depresssion.

Our ﬁndings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated

dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in

recreational users. We recommend large-scale clinical trials that include multiple doses of ketamine and long-term

follow up to assess the safety of long-term regular use.

Introduction

Major depression aects about 350 million people, making

it the leading cause of disability worldwide.

1,2

Anti-

depressant treatments targeting the monoamine system

alleviate depressive symptoms in only 50% of patients,

and rates become substantially lower in those whose

depression has not responded adequately to two or more

adequate antidepressant trials.

Moreover, these treatments

have a long onset of action, usually 3–4 weeks.

5,6

Hence,

there is an indisputable need for more ecacious and

rapidly acting antidepressants, with ketamine being a key

candidate. However, have investigations on ketamine in

depression thus far addressed essential factors such as

acute and long-term safety?

A balanced assessment of an intervention requires

investigation of both beneﬁts and harms. Usually

designed to evaluate treatment ecacy or eectiveness,

randomised controlled trials are often completed in a

short period of time, using a limited number of doses

and a relatively small number of participants. These

trials are known to be poor at identifying and reporting

harms,

which can lead to a misconception that a given

intervention is safe when its safety is actually unknown.

Since Berman and colleagues, in 2000,

reported the

results of their initial pilot placebo-controlled trial

investigating ketamine for the treatment of depression,

a plethora of articles, including original studies,

narrative reviews, and meta-analyses, have been

published, endorsing the ecacy of ketamine in

depression. Only a few of the original studies, however,

were randomised controlled trials or systematically

assessed ketamine’s ecacy and safety compared to

placebo or a control drug in patients with depression.

To date, ﬁndings from 20 randomised controlled trials

have been reported, which all together include

430 participants who received ketamine. Most of these

were proof of concept studies and examined the ecacy

of a single dose only, and only a small number

comprehensively assessed ketamine’s safety, tolerability,

and abuse potential. Very few examined the safety (or

ecacy) of repeated treatments, relative to placebo or

control treatment, although repeated treatments are

increasingly being used in open label studies,

10–17

case

studies,

18–33

and some clinical services.

Importantly, safety concerns have been reported in

other patient groups exposed to ketamine, such as

individuals with chronic pain, and recreational users.

Reviews, including from WHO,

highlighted urinary

tract symptoms as a well-documented side-eect of

ketamine and listed liver toxicity, cognitive changes, and

dependence as potential harms.

In 2012, Morgan and

Curran,

on behalf of the Independent Scientiﬁc

Committee on Drugs, concluded that frequent, daily use

of ketamine is associated with ulcerative cystitis and

neurocognitive deﬁcits in working and episodic memory;

they also reported that many frequent users are

concerned about addiction.

Despite the 15 years that have passed since Berman

and colleagues’ report, there remains a large gap in

knowledge regarding the long-term ecacy of ketamine

in depression, potential long-term safety issues, and the

absence of approved clinical guidelines for its use. With a

growing interest in ketamine as a treatment for

depression, as well as the increasing use of repeated

dosing in both clinical and research settings,

37–40

acute

and long-term safety issues must be further explored and

systematically assessed. In this systematic review, we

aggregate and analyse reporting of data on the safety of

ketamine in depression and comment on experience

from human clinical trials to date.

Methods

Search strategy and selection criteria

We followed PRISMA reporting guidelines in this

systematic review. Studies were eligible for inclusion if

they reported ﬁndings with adult human populations who

had a validated diagnosis of unipolar or bipolar depression

and had received one or more doses of ketamine (any

administration route, frequency of dose, and time course

were accepted). Studies also had to describe changes in

depression status as a primary outcome measure.

Exclusion criteria included: animal trials; studies that

were non-original or mechanistic in nature; studies that

described paediatric or adolescent population outcomes

Lancet Psychiatry 2018;

5: 65–78

Published Online

July 27, 2017

http://dx.doi.org/10.1016/

S2215-0366(17)30272-9

New South

Wales Institute of

Psy

chiatry, Sydney, NSW,

Australia (B Short MD); School

of Psychiatry, University of

New South Wales, Sydney,

NSW, Australia (B Short, J Fong,

V Galvez MD, Prof C K Loo MD);

Black Dog Institute, Sydney,

NSW, Australia (B Short,

V Galvez, Prof C K Loo);

St George Hospital, Sydney,

NSW, Australia (Prof C K Loo);

Wesley Hospital, Sydney, NSW,

Australia (Prof C K Loo); and

University of Otago, Dunedin,

Otago, New Zealand

(W Shelker MD)

Correspondence to:

Prof Colleen K Loo, Black Dog

Institute, Sydney, NSW 2031,

Australia

colleen.loo@unsw

.edu.au

www.thelancet.com/psychiatry Vol 5 January 2018

Review

only; studies that described other disorders of primary

interest, unless a patient with depression was included

(ie, pain, ﬁbromyalgia, suicidality, post-traumatic stress

disorder, recreational drug use); other intervention of

primary interest (eg, vagal nerve stimulation); studies

that included electroconvulsive therapy as a concomitant

intervention; and studies that reported on other

NMDA-receptor antagonist outcomes only (eg, nitrous

oxide, MK-0657, AZD6765). No restrictions were imposed

on language, and articles in foreign languages were

translated to English.

We searched MEDLINE, PubMed, PsycINFO, and

Cochrane Database for articles published from Jan 1, 1999,

to Dec 30, 2016, with the terms: “ketamine* AND (depress*

OR aective* OR mood* OR bipolar*) AND (safe* OR

side* OR adverse*)”. The initial database search was done

by three authors (BS, JF, WS) independently to ensure

reproducibility.

Two authors (JF, WS) did a two-step literature search;

when a title or abstract seemed to describe a study eligible

for inclusion, the full article was reviewed to assess its

relevance based on the inclusion criteria. Any disputes in

results were settled by consensus. Any discrepancies

between the two authors were resolved by consultations

with a senior author.

Although randomised clinical trials provide the most

reliable estimates of eect, rare serious adverse events or

long-term adverse eects are unlikely to be detected. We

therefore included many types of study designs.

Letters

or comments to editors were included if they reported on

a case study or series.

We collected information about study design, sample

characteristics, ketamine administration details (route,

dosage, number of doses), health screening before

ketamine administration, pre-existing medical morbidity,

concomitant medications, and timing of side-eects

assessment. Using the same time deﬁnitions, we also

collected information on which speciﬁc side-eects were

reported to have occurred (we considered a side-eect

as having occurred if the report listed its occurrence

in at least one patient); and, where relevant, whether

structured assessment tools or questionnaires were used

to assess adverse eects or safety. Each article was

quality-appraised with a relevant appraisal checklist or

tool (appendix).

Analysis

Initially, we took a broad approach to assessing potential

side-eects of ketamine for depression to detect a variety

of adverse eects or events, whether known or previously

unrecognised. We then categorised adverse eects into

subgroups (psychiatric, psychotomimetic or dissociative,

cardiovascular, neurological [including cognitive], and

other side-eects) to include the side-eects that had

been reported most frequently.

In accordance with the Cochrane Adverse Eects

Methods Group approach,

we addressed the following

issues that aect data quality: (1) selective outcome

reporting; (2) withdrawal or drop-out; and (3) presence of

a control group. For selective outcome reporting, we

identiﬁed whether, and to what extent, side-eects were

assessed and reported, which approach was used for

assessing side-eects (active surveillance [ie, method

described for actively enquiring about side-eects] versus

passive monitoring [no method for active enquiry

described, thus reports considered to represent side-

eects spontaneously reported by patients]), whether

structured scales or questionnaires for the assessment of

side-eects were used, whether side-eects were reported

systematically (ie, both presence and absence of side-

eects were reported) or ad hoc (ie, only reported if they

occurred), and the timeframe in which side-eects had

been assessed and reported (ie, immediately after a single

dose [acute], after repeated doses [cumulative], or at least

2 weeks after the last dose [long term]). To analyse

Figure 1: Study selection

ECT=electroconvulsive therapy. NMDA=N-methyl-D-aspartate. *Unless a patient with depression was included

(ie, pain, ﬁbromyalgia, suicidality, post-traumatic stress disorder, recreational drug use). †Nitrous oxide, MK-0657,

AZD6765.

103 records included

95 full-text articles assessed

for eligibility

35 full-text articles excluded

1 animal trial

1 paediatric and adolescent population

outcomes only

5 other disorders of primary interest*

1 ECT as a concomitant intervention

1 other NMDA-receptor antagonists only†

26 non-original research (ie, duplication,

opinion or review article)

60 studies included in

qualitative synthesis

60 studies included in review

20 randomised controlled trials

17 open-label trials

20 case series or reports

3 retrospective studies

591 records screened

186 records did not meet inclusion criteria

303 records met exclusion criteria

23 records identiﬁed through other sources568 records identiﬁed by database searches

IdentiﬁcationScreeningEligibilityIncluded

See Online for appendix

www.thelancet.com/psychiatry Vol 5 January 2018

Review

Number

patients

who

received

ketamine

Route; dose Reporting period; reported measures; reporting form

Psychiatric or psychotomimetic

side-eﬀects*

Cardiovascular side-eﬀects Neurological or cognitive

side-eﬀects

Other side-eﬀects

Randomised controlled trials

Berman et al

(2000)

7 Intravenous;

single

Short term†; BPRS, VAS;

systematic

·· ·· ··

Kudoh et al

(2002)

60‡ Intravenous;

single

·· Short term†; vital signs; ad hoc Short term†; CAM; ad hoc Short term; nasopharyngeal

temperature, end-expiratory oxygen

and carbon dioxide, VAS-pain; ad hoc

(systematic for VAS-pain)

Zarate et al

(2006)

17 Intravenous;

single

Short term, cumulative†; BPRS,

YMRS, VAS, BDI; systematic

Short term; not speciﬁed; ad hoc Short term; measures not

speciﬁed; ad hoc

Short term; measures not speciﬁed;

ad hoc

Diazgranados

et al (2010)

13 Intravenous;

single

Short term, cumulative, long

term†; HAM-D(17), HAM-A, BDI,

BPRS, YMRS, CADSS, VAS;

systematic

Short term†; vital signs, oximetry,

echocardiogram; ad hoc

Reporting period not speciﬁed;

measures not speciﬁed; ad hoc

Short term, long term†; blood cell

counts, electrolyte panels, LFTs,

ketamine and metabolites blood

concentrations; systematic

Zarate et al

(2012)

14§ Intravenous;

single

Short term, long term†;

HAM-D(17), HAM-A, BDI, BPRS,

YMRS, CADSS, VAS; systematic

Short term, long term†; vital signs,

oximetry, echocardiogram; ad hoc

Reporting period not speciﬁed;

measures not speciﬁed; ad hoc

Short term, long term†; blood cell

counts, electrolyte panel, LFTs;

systematic

Murrough

et al (2013)

47¶ Intravenous;

single

Short term†; CADSS, BPRS+;

systematic

Short term†; heart rate, blood

pressure, oximetry,

echocardiogram; systematic

Short term†; PRISE, MCCB;

systematic

Short term†; PRISE; systematic

Singh et al

(2013)

30 Intravenous;

multiple

Short term†; unspecified; ad hoc Short term†; heart rate, blood

pressure, oximetry; ad hoc

·· Short term; unspeciﬁed; ad hoc

Sos et al

(2013)

27 Intravenous;

single

Short term†; BPRS; ad hoc Reporting period not speciﬁed;

measures not speciﬁed; ad hoc

Reporting period not speciﬁed;

measures not speciﬁed; ad hoc

Short term; ketamine and metabolite

concentration in blood; ad hoc

Ghasemi et al

(2014)

9 Intravenous;

multiple

·· Short term, cumulative†; heart

rate, blood pressure, oximetry;

systematic

·· ··

Lai et al

(2014)

4 Intravenous;

multiple

Short term, cumulative†; BPRS,

YMRS, CADSS; systematic

Short term, cumulative†; heart

rate, blood pressure, oximetry;

ad hoc

Short term, cumulative†; SAFTEE,

orientation, simple or complex

reaction time; systematic

Short term, cumulative†; SAFTEE;

ad hoc

Lapidus et al

(2014)

18 Intranasal;

single

Short term†; CADSS, BPRS+,

YMRS; systematic

Short term†; heart rate, blood

pressure; systematic

Short term†; SAFTEE; systematic Short term†; SAFTEE, ketamine

concentration in blood; systematic

Murrough

et al (2015)

12 Intravenous;

single

Short term†; BPRS, CADSS, YMRS,

C-SSRS; ad hoc

Short term†; heart rate, blood

pressure; ad hoc

Short term, cumulative,

long term†; PRISE; ad hoc

Short term, cumulative, long term†;

PRISE; ad hoc

Hu et al

(2015)

13 Intravenous;

single

Short term, long term†; BPRS,

YMRS, CADSS; systematic

Short term†; heart rate, blood

pressure, echocardiogram,

oximetry, respiratory rate; ad hoc

Reporting period not speciﬁed;

measures not speciﬁed; ad hoc

Short term†; author created checklist

of so-called common somatic

side-eﬀects; systematic

Lenze et al

(2016)

20 Intravenous;

single

Short term†; BPRS+; systematic Short term, cumulative†; blood

pressure, echocardiogram; ad hoc

Short term†; clinical and adverse

events checklists; systematic

Short term†; clinical and adverse

events checklist, LFTs; systematic

Li et al

(2016)

32 Intravenous;

single

Short term†; BPRS+; mix of

systematic and ad hoc

·· ·· Short term; measures unclear; ad hoc

Loo et al

(2016)

15 Intravenous,

intramuscular,

subcutaneous;

multiple

Short term, cumulative†; BPRS+,

YMRS, CADSS; systematic

Short term, cumulative†; heart

rate, blood pressure; systematic

Short term, cumulative†;

SAFTEE, orientation, simple or

complex reaction time; ad hoc

Short term, cumulative†; SAFTEE,

ketamine concentration in blood;

ad hoc

Singh et al

(2016)

35 Intravenous;

multiple

Short term, cumulative†; BPRS+,

CADSS, C-SSRS; systematic

Short term, cumulative†; vital

signs, oximetry, echocardiogram;

systematic

Short term, cumulative,

long term; unspeciﬁed;

systematic

Short term, cumulative, long term†;

physical examination, lab tests (not

speciﬁed),ketamine and metabolite

concentration in blood; systematic

Jafarinia et al

(2016)

20 Oral; multiple ·· Monitoring period not speciﬁed†;

physical examination,

echocardiogram; ad hoc

Monitoring period not

speciﬁed†; adverse events

checklist; ad hoc

Monitoring period not speciﬁed†;

adverse events checklist, VAS pain,

open-ended question; ad hoc

Downey et al

(2016)

21 Intravenous;

single

Short term†; CADSS; ad hoc Monitoring period not speciﬁed;

measures not speciﬁed;

not available

Monitoring period not speciﬁed;

measures not speciﬁed; ad hoc

Monitoring period not speciﬁed;

measures not speciﬁed; not available

(Table 1 continues on next page)

www.thelancet.com/psychiatry Vol 5 January 2018

Review

Number

patients

who

received

ketamine

Route; dose Reporting period; reported measures; reporting form

Psychiatric or psychotomimetic

side-eﬀects*

Cardiovascular side-eﬀects Neurological or cognitive

side-eﬀects

Other side-eﬀects

(Continued from previous page)

George et al

16 Subcutaneous;

multiple

Short term, cumulative†; BPRS,

YMRS CADSS; systematic

Short term, cumulative†; heart

rate, blood pressure; systematic

Short term, cumulative†;

orientation, reaction times, neuro-

psychological tests; systematic

Short term, cumulative, long term†;

SAFTEE—modiﬁed, urinary problems

checklist, LFTs; systematic

Non-randomised controlled trials or open label trials

Phelps et al

(2009)

26 Intravenous;

single

Short term†; BPRS, CADSS; ad hoc

aan het Rot

et al (2010)

10 Intravenous;

multiple

Short term, cumulative†; BPRS+,

CADSS; systematic

Short term, cumulative†; heart

rate, blood pressure, oximetry,

respiratory rate, echocardiogram;

systematic

Short term, cumulative; SAFTEE-

SI; systematic

Short term, cumulative, long term;

SAFTEE-SI, weight; ad hoc

Mathew et al

(2010)

26|| Intravenous;

single

Short term†; BPRS+, CADSS, VAS,

YMRS; systematic

Short term†; heart rate, blood

pressure, oximetry,

echocardiogram; systematic

Short term, long term†; SAFTEE,

MATRICS battery (MCCB);

systematic

Short term, long term†; SAFTEE,

physical examination, weight, baseline

blood tests, LFTs, urinanalysis;

systematic

Ibrahim et al

(2011)

40** Intravenous;

single

Short term†; CADSS; systematic ·· ·· ··

Larkin et al

(2011)

14 Intravenous;

single

Short term†; YMRS, BPRS+;

systematic

Short term†; vital signs; ad hoc ·· Short term†; weight; ad hoc

Valentine

et al (2011)

10 Intravenous;

single

Short term†; CADSS, BPRS+

HAM-A; systematic

Short term†; vital signs;

systematic

·· ··

Ibrahim et al

(2012)

42†† Intravenous;

single

Short term, long term†; BPRS,

CADSS, YMRS, SSI; systematic

Short term†; vital signs, oximetry,

echocardiogram; systematic

·· Short term, long term†; blood cell

counts, electrolyte panels, LFTs,

ketamine and metabolites

concentration in blood, weight;

systematic

Zarate et al

(2012)

67** Intravenous;

single

Short term†; BPRS, BPRS+,

CADSS; systematic

·· ·· Ketamine and metabolite

concentration in blood; systematic

Irwin et al

(2013)

14 Oral; multiple Short term, cumulative†; adverse

symptom checklist, SRA, KPSS;

systematic

Short term, cumulative†; adverse

symptom checklist; systematic

Short term, cumulative†; adverse

symptom checklist, MMSE;

systematic

Short term, cumulative†; adverse

symptom checklist, VAS-pain, BPI-SF;

systematic

Murrough

et al (2013)

14‡‡ Intravenous;

multiple

Short term, cumulative†; BPRS+,

CADSS, YMRS, VAS; systematic

Short term, cumulative†; heart

rate, blood pressure, oximetry;

systematic

Short term, cumulative†;

SAFTEE; systematic

Short term, cumulative†; SAFTEE;

systematic

Rasmussen

et al (2013)

10 Intravenous;

multiple

Short term, cumulative†; YMRS,

BPRS, CGI, SSI, SSF

Short term, cumulative†; blood

pressure, oximetry,

echocardiogram; systematic

Short term; measures not

speciﬁed; ad hoc

Short term; measures not speciﬁed;

ad hoc

Diamond

et al (2014)

28 Intravenous;

multiple

Short term, cumulative†; BPRS,

VAS; ad hoc

Monitoring period not speciﬁed;

measures not speciﬁed; ad hoc

Short term, cumulative, long

term†; AMI-SF, AFT, story recall,

ECT-MQ; systematic

Monitoring period not speciﬁed;

measures not described; ad hoc

Shiroma et al

(2014)

14 Intravenous;

multiple

Short term, cumulative†; BPRS+,

CADSS, VAS, CGI; systematic

Short term†; heart rate, blood

pressure, respiratory rate,

oximetry, mAldrete; systematic

Short term, cumulative†; MMSE,

mAldrete; systematic

Short term; measures note speciﬁed;

ad hoc

Allen et al

(2015)

17 Intravenous;

multiple

·· Short term, cumulative; heart rate,

blood pressure, oximetry;

reporting form not specied; ad hoc

·· ··

Ionescu et al

(2015)

3 Intravenous;

single

Short term†; CADSS, HAM-A;

ad hoc

·· ·· ··

Kantrowitz

et al (2015)

8 Intravenous;

single

Monitoring period not speciﬁed;

measures not speciﬁed; ad hoc

·· Monitoring period not speciﬁed;

measures not speciﬁed; ad hoc

Monitoring period not speciﬁed;

measures not speciﬁed; ad hoc

Cusin et al

(2016)

14 Intravenous;

multiple

Short-term, cumulative†; BPRS,

CADSS, CGI, C-SSRS; systematic

Short term, cumulative†; heart

rate, blood pressure, respiratory

rate, oximetry, echocardiogram;

systematic

Short term, cumulative†;

SAFTEE, CPFQ; ad hoc

Short term, cumulative†; SAFTEE,

QLES-Q; systematic

(Table 1 continues on next page)

www.thelancet.com/psychiatry Vol 5 January 2018

Review

Number

patients

who

received

ketamine

Route; dose Reporting period; reported measures; reporting form

Psychiatric or psychotomimetic

side-eﬀects*

Cardiovascular side-eﬀects Neurological or cognitive

side-eﬀects

Other side-eﬀects

(Continued from previous page)

Case studies and case series

Correll et al

(2006)

2 Intravenous;

multiple

Short term; measures not

speciﬁed; ad hoc

Short term†; heart rate, blood

pressure; ad hoc

·· Reporting period not speciﬁed†;

measures not specified; ad hoc

Stefanczyk-

Sapieha et al

(2008)

1 Intravenous;

multiple

Short term; measures not

speciﬁed; ad hoc

Short term†; vital signs, oximetry;

ad hoc

·· Short term†; ESAS; ad hoc

Paul et al

(2009)

2 Intravenous;

multiple

Short term, cumulative†;

measures not specified; ad hoc

Short term, cumulative†; blood

pressure, echocardiogram,

oximetry; systematic

·· Short term, cumulative†; measures not

specified; ad hoc

Paslakis et al

(2010)

4 Oral; multiple Short term, cumulative; unclear

measures; ad hoc

Short term, cumulative†; heart

rate, respiratory rate; ad hoc

Short term, cumulative; unclear

measures; ad hoc

Short term, cumulative†; routine

laboratory tests; ad hoc

Irwin et al

(2010)

2 Oral; single Short term†; BPRS, YMRS;

systematic

·· Short term†; MMSE; systematic Short term†; adverse symptom

checklist, FIBSER, VAS-pain; systematic

Murrough

et al (2011)

1 Intravenous;

multiple

·· ·· ·· ··

Blier et al

(2012)

1 Intravenous;

multiple

Short term, cumulative; measures

not speciﬁed; ad hoc

·· Cumulative†; MoCA; systematic Short term, cumulative; measures not

speciﬁed; ad hoc

Cusin et al

(2012)

2 Intravenous,

intranasal, oral,

intramuscular;

multiple

Short term, cumulative; measures

not speciﬁed; ad hoc

·· ·· ··

Lara et al

(2013)

26 Sublingual;

multiple

Reporting period not speciﬁed;

unclear measures; ad hoc

·· ·· Reporting period not speciﬁed; unclear

measures; ad hoc

Messer et al

(2013)

1 Intravenous;

multiple

Short term, cumulative; measures

not speciﬁed; ad hoc

Short term, cumulative†; vital

signs; ad hoc

Short term, cumulative;

measures not speciﬁed; ad hoc

Short term, cumulative; measures not

speciﬁed; ad hoc

Niciu et al

(2013)

2 Intravenous;

single

Short term†; CADSS, Y-BOCS;

ad hoc

·· ·· Short term; measures not speciﬁed; ad

hoc

Segmiller

et al (2013)

1 Intravenous;

multiple

Short term; measures not

speciﬁed; ad hoc

·· ·· ··

Segmiller

et al (2013)

6 Intravenous;

multiple

Short term; measures not

speciﬁed; ad hoc

·· ·· ··

Szymkowicz

et al (2013)

3 Intravenous;

multiple

Short term, cumulative; measures

not speciﬁed; ad hoc

Short term, cumulative†; vital

signs; ad hoc

Short term, cumulative;

measures unspeciﬁed; ad hoc

Short term, cumulative; measures

unspeciﬁed; ad hoc

Womble

(2013)

1 Intravenous;

single

·· Short term†; heart rate, blood

pressure, oximetry; systematic

·· Short term; measures not speciﬁed; ad

hoc

Zanicotti

et al (2013)

1 Intramuscular;

multiple

Short term, cumulative; measures

not speciﬁed; ad hoc

Short term†; heart rate, blood

pressure, oximetry; systematic

Short term, cumulative;

measures unspeciﬁed; systematic

··

Aligeti et al

(2014)

1 Intravenous;

single

Short term, long term; measures

not speciﬁed; ad hoc

Short term†; blood pressure,

heart rate, respiratory rate,

oximetry, echocardiogram;

systematic

·· ··

Galvez et al

(2014)

1 Subcutaneous;

multiple

Short term, cumulative†; BPRS,

CADSS; ad hoc

·· ·· Reporting period not speciﬁed;

measures not speciﬁed; ad hoc

Gosek et al

(2014)

5 Intravenous;

multiple

Short term†; CADSS, CGI; ad hoc Short term†; basic life

parameters, echocardiogram;

ad hoc

Short term; measures not

speciﬁed; ad hoc

··

Hassamal

et al (2015)

1 Intravenous;

multiple

Short term, cumulative; measures

not speciﬁed; ad hoc

Short term†; vital signs;

systematic

Short term, cumulative; measures

not speciﬁed; ad hoc

Short term, cumulative; measures not

speciﬁed; ad hoc

(Table 1 continues on next page)

www.thelancet.com/psychiatry Vol 5 January 2018

Review

withdrawal or drop-out, we gathered as much information

as possible to avoid directly interpreting such data as

surrogate markers for safety or tolerability because of

potential bias. We assessed the presence of a control group

in order to distinguish between adverse events (ie, those

which appear after intervention onset) and adverse eects

(ie, adverse events for which causality is likely).

A meta-analysis was initially planned, but after data

extraction it was deemed that quantitative analysis via

meta-analytical methods was not appropriate for the

side-eects reported because the articles reviewed

were clinically diverse, including a variety of dierent

administrative routes and doses with dierent control

comparators, dierences in reporting methods (including

non-speciﬁc qualitative statements about side-eects), and

bias for some of the individual studies (including reporting

bias). Thus, a qualitative review of data was undertaken.

Results

We included 60 studies in our analysis (ﬁgure 1, table 1),

which included 899 patients who had received at least

one dose of ketamine (table 2). Most study reports did

not include a placebo or control group (ﬁgure 2). Acute

side-eects were assessed in 55 (92%) studies, whereas

cumulative side-eects were analysed in 24 (40%)

studies, and long-term side-eects were assessed in

12 (20%) studies (ﬁgure 3). In studies that did include

a placebo or comparator intervention, side-eects

across all categories were more commonly reported in

patients who received ketamine.

Acute psychiatric side-eects from ketamine were

described in 23 (38%) studies, whereas psychotomimetic

or dissociative side-eects were described in 43 (72%)

studies, some of which used structured scales (ﬁgure 4).

Overall, the timepoints used for measurements diered

between studies; however, any changes in score were

generally self-limiting.

The most common acute psychiatric side-eect

was anxiety, followed by agitation or irritability,

euphoria

or mood elevation, delusions or unusual thoughts,

panic, and apathy. Less common side-eects were

detachment, emotional blunting, psychosis, emotional

lability, craving attention, and formal-thought disorder.

When symptoms were delayed, such as with anxiety,

worsening depression or suicidality, or both, and

hypomania, it was unclear if they were explicitly linked

to the ketamine treatment. An isolated case of a suicide

attempt was reported in one study.

Across all the

studies analysed, the most common psychiatric reason

for withdrawal from a trial was worsening mood

(12 participants), followed by anxiety (six participants)

and suicidal ideation (ﬁve participants). Less common

psychiatric reasons for withdrawal included panic attack

(two participants) and irritability (one participant). An

Number

patients

who

received

ketamine

Route; dose Reporting period; reported measures; reporting form

Psychiatric or psychotomimetic

side-eﬀects*

Cardiovascular side-eﬀects Neurological or cognitive

side-eﬀects

Other side-eﬀects

(Continued from previous page)

Retrospective studies

Quinones et

al (2012)

Un-

speciﬁed

Intravenous;

single

·· Short term†; heart rate, blood

pressure, respiratory rate,

oximetry; ad hoc

·· Short term; temperature; ad hoc

Iglewicz et al

(2015)

31 Oral,

subcutaneous;

multiple

Short term, cumulative; measures

not speciﬁed; ad hoc

·· ·· Short term, cumulative; measures not

speciﬁed; ad hoc

Nguyen et al

(2015)

17 Transmucosal;

multiple

·· ·· Reporting period not speciﬁed;

measures not speciﬁed; ad hoc

··

Short-term side-eﬀect assessments were completed within 4 h. Cumulative side-eﬀect assessments were completed after multiple doses. Long-term side-eﬀect assessments were completed at least

2 weeks after last dose. BDI=Beck depression inventory. BPI-sf=brief pain inventory short form. BPRS=brief psychiatric rating scale. BPRS+=brief psychiatric rating scale positive symptom subscale.

CADSS=clinician administered dissociative states scale. CAM=confusion assessment method. CGI=clinical global impression. CPFQ=cognitive and physical functioning questionnaire. C-SSRS=Columbia

suicide severity rating scale. ESAS=Edmonton system assessment system. FIBSER=frequency, intensity and burden of side-eﬀects rating. HAM-A=Hamilton anxiety rating scale. HAM-D(17)=Hamilton

rating scale for depression (17-item). KPS=Karnofsky performance status scale. MATRICS=Measurement and treatment research to improve cognition in schizophrenia. MCCB=MATRICS consensus

cognitive battery. MMSE=mini-mental state exam. MoCA=Montreal cognitive assessment. mAldrete=modiﬁed Aldrete scoring system. PRISE=patient-related inventory of side-eﬀects. QLES-Q=quality of

life enjoyment and satisfaction questionnaire. SAFTEE=systematic assessment for treatment emergent eﬀects. SAFTEE-SI=systematic assessment for treatment emergent eﬀects speciﬁc inquiry.

SRA=suicide risk assessment. SSI=scale for suicidal ideation. SSF=suicide status form. VAS=visual analogue scale. YMRS=Young mania rating scale. *Other than primary outcome measures. †Active

assessment. ‡25 of these patients were administered ketamine over a reduced infusion time period. §Replicated study design of Diazgranados et al (2010).

¶Neurocognitive outcomes published in

separate publication using same study design and sample as in Murrough et al (2015).

||Neurocognitive outcomes published in separate publication using same study design and sample as in

Murrough et al (2014).

**Possible sample overlap with other studies published by this group (Zarate et al [2006];

Diazgranados et al [2010];

Zarate et al [2012];

and Phelps et al [2009]

).††Some

patient results also included in the report by Ionescu et al (2014).

‡‡Some patient results were also reported by aan het Rot et al (2010).

Table 1: Study design, patient and dosing information, side-eﬀect assessment, and reporting

www.thelancet.com/psychiatry Vol 5 January 2018

Review

absence of psychosis or mania as a potential side-eect

was reported in ﬁve (8%) studies.

The most common psychotomimetic side-eect

reported was dissociation, followed by perceptual dis-

turbance, odd or abnormal sensation,

derealisation,

hallucinations, feeling strange, weird, bizarre, or unreal,

and depersonalisation.

No long-term psychotomimetic

side-eects were reported; however, most studies

assessed for psychotomimetic side-eects only over the

short term (usually within 4 h post-ketamine dose).

Dissociation was the only psychotomimetic cause cited

for withdrawal from studies (two participants in total).

The absence of psychotomimetic or dissociative eects

was reported in ﬁve (8%) studies.

In general, studies using the intravenous route of

administration tended to report more psychotomimetic

or dissociative side-eects than those that used other

routes of administration (eg, oral, subcutaneous, intra-

muscular). 36% of non-intravenous studies reported

psychotomimetic side-eects, compared with 72% of

intravenous studies.

Of the 60 studies included in this analysis, 23 (38%)

reported acute changes in the cardiovascular status of

patients. The most common cardiovascular changes were

increased blood pressure and increased heart rate.Other

reported cardiovascular side-eects included palpitations

or arrhythmia, chest pain, tightness, or pressure, dizziness

on standing, decreased blood pressure, and decreased

heart rate. Five patients were withdrawn because of

cardiovascular side-eects. Most cardiovascular eects

were reported as occurring during or immediately after

intravenous ketamine administration. In general, these

eects resolved within 90 min of the administered dose.

The most common neurological side-eects cited were

headache and dizzi ness.

Less common neuro logical side-

eects included sedation or drowsiness, faintness or

light-headedness, poor coordination or un steadiness,

and

tremor or involuntary movements.

Most studies reported

only short-term neurological eects.

Cognitive side-eects included poor memory or memory

loss, poor concentration, confusion, and cognitive

impairment or diminished mental capacity. Similarly, if

cognitive side-eects were described, these were reported

over the short term only. Potential cognitive side-eects

were not assessed in most studies.

Numerous other side-eects were reported in

32 (53%) studies, with the greatest variety reported in

patients receiving intravenous ketamine. These side-

eects mainly related to the gastrointestinal, ocular,

respiratory, and urological systems.

The most frequently reported other side-eects

were blurred vision

and nausea.

Less common side-

eects included insomnia or sleep disturbance, decreased

energy, general malaise, or fatigue,

restlessness,

dry

mouth, vomiting,

and crying or tearfulness.

Urinary side-eects were assessed in only ﬁve studies.

Liver function tests were speciﬁcally reported to have been

completed in seven studies, with two study outcomes

including abnormalities post-ketamine dose.

55,61

Only

two studies enquired about the development of ketamine

dependence or abuse.

23,26

Scales (eg, SAFTEE, PRISE) to systematically assess

other side-eects were used in 15 (25%) studies. Most

study groups relied on passive monitoring of treatment-

emergent adverse events, and only a few groups followed

Figure 2: Study types and design

Study types

Randomised controlled

trial

Open label

Case study or series

Retrospective

Study design

Ketamine compared with

placebo

Ketamine compared with

active control

Ketamine dosing

comparisons

No placebo or control

Number of

published

articles*

Number of

patients who

received

ketamine†

Number of

patients who

received multiple

doses†

Intravenous 49 737‡ 214

Per oral 6 72 66

Intramuscular 3 7 7

Subcutaneous 4 25 25

Intranasal 2 18 1

Sublingual 1 26 26

Transmucosal 1 17 17

Total ·· 902§ 356

*Some studies used multiple administrative routes. †Values are approximations,

as number of doses per route for some patients was unclear in some of the

studies. ‡One study,

in which ketamine was administered intravenously, had an

unspeciﬁed number of patients. § Three patients received more than one

ketamine administration route.

Table 2: Total number of published articles and patients in the reviewed

studies, by ketamine administration route

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Review

up on these other adverse events beyond the acute

treatment period. Thus, the long-term trajectory and

consequences of these reported other side-eects are

largely unknown.

If side-eects were assessed for, they were

predominantly reported in an ad-hoc fashion. Psychiatric

or psycho tomimetic side-eects were systematically

reported in only 25 (42%) studies; cardiovascular side-

eects were systematically reported in 19 (32%) studies;

neurological or cognitive eects were systematically

reported in 14 (23%) studies; and all other side-eects

were systematically reported in 14 (23%) studies. When

considering the side-eect reporting from randomised

controlled trials only, the most common acute side-eects

were reported at similar rates as for other study designs.

However, long-term side-eect risks or other potential

side-eects, including cognition, urinary tract symptoms,

or dependency risk, were rarely assessed or commented

on in randomised controlled trials (ﬁgure 5).

Discussion

We systematically reviewed 288 published reports of

studies in which ketamine was administered to people

who had depression. Our objective was to identify the

main side-eects related to this intervention and to

discern whether dierences were apparent between

single (acute) versus repeated dosing (cumulative and

long-term). Side-eects were categorised to facilitate

collation and analysis of results; notably, most people

receiving ketamine had acute side-eects. In summary,

our main ﬁndings were: (1) acute side-eects are common

after a treatment of ketamine; (2) active assessment,

surveillance, and reporting of side-eects during trials of

ketamine for patients with depression are inadequate;

(3) most of the side-eects reported were associated with

ketamine given intravenously; (4) most of the assessed

side-eects were reported to occur immediately after

single-dose administration (acute); (5) the most common

side-eects to be reported were headache, dizziness,

dissociation, elevated blood pressure, and blurred vision

(ﬁgure 5); (6) most side-eects were reported to have

resolved shortly after dose administration; (7) psychiatric

side-eects were also apparent, the most common being

anxiety; (8) many side-eects were assessed through

passive monitoring only; (9) if side-eect assessment was

completed, it was predominantly reported in ad-hoc form;

and (10) from the analysis, we could only draw conclusions

regarding single dosing and acute side-eects because

insucient data were available regarding the side-eects

of repeated dosing and possible cumulative and long-

term risks.

Passive monitoring of side-eects relies on spontaneous

reports and is very helpful to detect new, rare, and serious

side-eects.

Active surveillance includes a preorganised

process to discover more information on side-eects,

including additional detail, which usually cannot be

achieved via passive monitoring methods.

An important

factor that has emerged from our literature analysis is the

inadequacy of active and structured inquiry of known or

potential side-eects. Although the brief psychiatric

rating scale, the clinician-administered dissociative states

Figure 3: Time period of reported ketamine side-eﬀects

Figure 4: Use of structured side-eﬀect enquiry and subgroups

(A) Proportion of studies that used structured side-eﬀect scales. (B) Number of studies that reported side-eﬀects

(shown per subgroup). BPRS=brief psychiatric rating scale. CADSS=clinician-administered dissociative states scale.

YMRS=Young mania rating scale. *Other than primary outcomes.

Number of studies

Acute Cumulative Long term

Time period of reported ketamine side-eﬀects

0 10 20 30 40 50 60 70

BPRS

CADSS

YMRS

Cardiovascular

No scale or active

monitoring

Proportion of studies (%)

Reported scale type

0 10 20 30 40 50

Psychiatric*

Psychotomimetic

or dissociative

side-eﬀects

Cardiovascular

Neurological or

cognitive

side-eﬀects

Other

Subgroups of reported side-eﬀects

Number of studies

Studies that described assessment for side-eﬀects

Studies that reported the occurrence of side-eﬀects

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Review

scale, and basic cardiovascular measures are used in

many studies, methods for assessing other categories

of side-eects, including neurological, cognitive, gastro-

intestinal, and urological side-eects, were not speciﬁcally

reported. This is particularly important in view of our

ﬁndings that neurological and other side-eects, when

considered categorically, were reported to occur just as

often as or more often than cardiovascular or psychiatric

side-eects. Although ketamine is considered a safe

drug for its principal approved application regarding

anaesthesia (which usually involves a single one-o

dose),

the prospect of ketamine use in depression will

likely entail multiple and repeated doses during a long

period of time.

Repeated use of ketamine in other adult populations,

including patients undergoing anaesthesia, patients with

chronic pain, and recreational users, has been linked

with urological toxicity, hepatotoxicity, cognitive deﬁcits,

and dependency risks. For example, in 2007, Shahani

and colleagues

ﬁrst described chronic users of ketamine

who developed severe genitourinary symptoms. Since

then, a large volume of additional reports associating

ketamine with bladder toxicity have described cystitis

and bladder dysfunction, an increase in urinary

frequency, urgency, dysuria, urge incontinence, and

occasionally painful haematuria.

85–87

Secondary renal

damage has also been described in severe cases,

and

Chen and colleagues

have published the ﬁrst case of

renal infarction after nasal insuation of ketamine.

Ketamine use has also been linked with urological

toxicity in patients receiving treatment for chronic pain,

with some patients developing genitourinary symptoms

after only 9 days of treatment.

89–91

More than 20% of people who use ketamine for

recreational purposes are estimated to have urinary tract

symptoms,

although investigators from Spain and

Hong Kong report a much higher prevalence (46% and

90%, respectively).

The mechanism by which ketamine

causes urological toxicity is not understood, but ﬁndings

from in-vitro studies have shown a direct interaction

between ketamine and the bladder urothelium,

94,95

and in

one study, ketamine exposure was associated with

apoptosis of urothelial cells.

The damage appears to be

dose related, and although initially thought to improve or

resolve entirely after cessation of ketamine use, this

might not be the case.

Ketamine has been reported to negatively aect the

liver and biliary tract. Noppers and colleagues

showed

that liver injury might occur after prolonged or repeated

infusion of ketamine, or both. Six patients were

scheduled to receive two continuous, intravenous, 100 h

ketamine infusions (infusion rate 10–20 mg/h) separated

by 16 days. Three patients developed hepatotoxicity after

the start of the second infusion. Other reports of liver

toxicity in users of recreational ketamine exist,

and

Bell

and Sear

100

have expressed serious concerns. The

mechanism by which ketamine causes liver injury is not

understood but might be related to metabolic events

causing increased lipid peroxidation and free radical

formation.

100

In a preclinical study, ketamine was found

to increase ﬂow resistance across the sphincter of Oddi,

101

but in a more recent study in human beings, ketamine

use in a single dose of 20 mg did not aect sphincter of

Oddi parameters.

102

Other authors have proposed that the

N-methyl-D-aspartate receptor antagonistic eect of

ketamine might cause smooth muscle relaxation and

subsequent dilatation of the biliary tree and gallbladder

dyskinesia via a central pathway.

103

Compared with healthy controls without a history of

drug abuse, people who use ketamine frequently can

also have severe impairments in both short-term and

long-term memory.

104

In a double-blind randomised

Figure 5: Most common side-eﬀects reported by studies and reporting of side-eﬀect occurrence in

randomised controlled trials

0 5 10 15 20 25 30 35 40

Headache

Dizziness

Dissociation

Increased blood pressure

Blurred vision

Nausea

Sedation or drowsiness

Faintness or light-headedness

Anxiety

Elevated heart rate

Proportion of studies (%)

Side-eﬀect

Number of studies

Headache

Dizziness

Dissociation

Increased blood pressure

Blurred vision

Sedation or drowsines

Faintness or light-headednes

Anxiety

Elevated heart rate

Nausea

Dependency risk

Urinary tract side-eﬀects

Cognition side-eﬀects

Side-eﬀect

Any study type

Randomised controlled trials

www.thelancet.com/psychiatry Vol 5 January 2018

Review

crossover study, Hartvig and colleagues

105

found that

short-term memory could be acutely impaired dose-

dependently by intravenous administration of 0·1 mg/kg

and 0·2 mg/kg, as assessed by a word recall test. Krystal

and colleagues

106

and Malhotra and colleagues

107

have

replicated these results. People who have become

chronic recreational ketamine users have a regionally

selective up-regulation of D1 receptor availability in the

dorsolateral prefrontal cortex, an eect also seen after

chronic dopamine depletion in animals.

108

These data

suggest that repeated use of ketamine aects prefrontal

dopaminergic transmission, a system involved in

working memory and executive function.

Data from studies of people with chronic pain and

depression have been less conclusive. In a study by

Koer and colleagues,

109

cognitive eects of ketamine in

patients treated for chronic pain were extensively assessed

with several neuropsychological tests before infusion and

at 6 weeks post-infusion; they concluded that ketamine

had no residual cognitive eects at 6 weeks. Murrough

and colleagues (2014

and 2015

) reported that low-

dose ketamine was associated with minimal acute

neurocognitive eects in patients with treatment-resistant

depression 40 min after ketamine infusion. They also

reported that any changes in cognition appeared to be

transient in nature, with no adverse neurocognitive

eects 7 days after treatment. In both Koer’s and

Murrough’s studies, however, the follow-up periods were

short, making it dicult to comment on long-term risks

associated with repeated use.

Another question raised from this literature review

relates to the safety of using ketamine in patients with

depression who might have other comorbid medical

disorders. It is unclear in many studies whether

comprehensive health screens were completed before

ketamine initiation. For instance, given that acute blood

pressure changes are commonly reported after a

ketamine dose, particularly if given intravenously, should

practitioners be more cautious in administering

ketamine to patients with a history of cardiovascular

disease? According to WHO, ketamine is contraindicated

in patients with moderate-to-severe hypertension,

congestive cardiac failure, or a history of cerebrovascular

accident.

110

Despite low doses of ketamine being used in

depression studies, caution should be taken if repeatedly

used. This concern is also reﬂected in the scientiﬁc

literature about chronic pain, in which investigators

conclude that ketamine use should be restricted because

of side-eects,

111

that rapid acting routes of administration

of ketamine such as injection or intranasal route should

be avoided, and doses should be kept as low as possible

for other administration routes.

112

Ketamine is a drug of recreational misuse. The

incidence of dependency is unknown, but ﬁndings from

both preclinical and clinical studies in the anaesthesia

setting have shown that repeated doses of ketamine are

associated with rapid development of tachyphylaxis,

and

in the scientiﬁc literature describing recreational misuse,

craving for ketamine, compulsive behaviour, and rapid

development of tolerance are common in people who use

ketamine frequently.

113

This phenomenon has also been

described in pigeons and monkeys, who repeatedly self-

administered freely available ketamine and at increasing

amounts with time.

114,115

Only a very few cases (fewer

than 15) of human ketamine dependence have been

described in the past 20 years,

116–121

including a recent

report of tolerance leading to escalating use of ketamine

in an individual with depression.

122

Repeated ketamine

administration in depression might be associated with

the risk of dependency in susceptible individuals. Despite

low ketamine doses being used in depression studies,

urological toxicity, liver function abnormalities, negative

cognitive eects, and risk of dependence might limit

the safe use of ketamine as a long-term antidepressant

treatment. These aspects require further careful

examination before ketamine is adopted as a clinical

treatment for depression.

Systematic reviews of side-eects can provide valuable

information to describe adverse events (frequency,

nature, seriousness), but they are hampered by a lack of

standardised methods to report these events and the fact

that side-eects are not usually the primary outcome of

included studies.

123–126

An important limiting factor in our

analysis was our inability to conduct a formal meta-

analysis because of the heterogeneity in the assessment

and reporting of side-eects between studies as well as

many dierences in study designs and methods and

because of the diculty of analysing the actual incidence

of side-eects versus the reporting of side-eects. Most

reports of the occurrence of a side-eect were qualitative,

using inconsistent terminology and varying timepoints,

and sometimes the reports did not specify the number of

patients who had the side-eect, but stated in generic

terms that the side-eect was observed to have occurred.

A major implication of our review ﬁndings is that data

for side-eects should be collected though active

surveillance in future ketamine-related depression

studies and side-eects potentially related to ketamine

should be reported systematically (panel). Structured

rating scales should be used to enquire about speciﬁc

potential side-eects that appear just after a treatment

Panel: Future research priorities

• Systematic assessment of ketamine’s eﬃcacy and safety in

patients with depression compared with placebo or a

control drug, particularly in repeated dose or long-term use

• Assessment of repeated dosing regimes, consideration of

comorbid physical health factors, and full reporting of

potential side-eﬀects

• A Ketamine Side Eﬀect Tool and a Ketamine Safety

Screening Tool are being developed and validated to assist

investigators in this area of research

www.thelancet.com/psychiatry Vol 5 January 2018

Review

dose, between doses, and during the long term. The

frequency of reported side-eects or adverse drug

reactions is greater when patients are directly questioned

than when unstructured methods are used.

127

Similarly,

screening before treatment begins would help identify

those patients who might be at high risk of particular

side-eects. This screening could include the collection

of information around comorbid physical health and

concomitant medications. We are developing and

validating the Ketamine Side Eect Tool and Ketamine

Safety Screening Tool for these purposes.

Most of the studies we identiﬁed used racemic

ketamine. Large depression trials using the S-isomer of

ketamine are now underway. The incidence and severity

of acute and long-term side-eects with R-isomers and

S-isomers of ketamine versus the racemic mixture, and

metabolites of these primary compounds, are questions

that remain to be answered.

Conclusion

Ketamine’s pharmacological proﬁle makes it an

interesting and possibly useful drug for the treatment of

refractory depression. Acute side-eects associated with

single-dose use in depression are common, although

generally transient and resolve spontaneously. High

doses and repeated administration have been associated

with potentially serious and possibly persistent toxic

eects both in patients treated for chronic pain and in

people who use recreational ketamine. These side-eects

include urological, hepatic, craving or dependence, and

cognitive changes. To date, these side-eects have not

been adequately assessed in studies investigating

ketamine use in depression. Almost all randomised

controlled trials assessed the safety of single sessions of

ketamine, but with only short-term follow up. The safety

of long-term, repeated ketamine dosing, as is increasingly

used in clinical practice, is therefore uncertain. Data on

the safety of this practice, including long-term outcomes,

are essential before ketamine can be used for clinical

treatment of depression. Further large-scale clinical trials

including patients with depression, which include

multiple doses of ketamine, long-term follow up, careful

monitoring, and reporting of all potential side-eects are

recommended.

Contributors

BS, JF, and WS completed the literature search. BS and JF collected data.

BS, FJ, VG, and WS extracted data. BS, VG, and CKL interpreted the

data. BS, VG, and CL wrote this paper. BS and JF compiled the tables.

BS, VG, and CKL developed the Ketamine Side Eect Tool, and JF

revised the references.

Declaration of interests

CKL declares fees for attending a Janssen Advisory Board Meeting.

All other authors declare no competing interests.

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