The efficacy and safety of ketamine for depression in patients with cancer: A systematic review

International Journal of Clinical and Health Psychology 24 (2024) 100428

Available online 15 December 2023

http://creativecommons.org/licenses/by/4.0/).

Original article

The efcacy and safety of ketamine for depression in patients with cancer:

A systematic review

Leila Azari

, Homa Hemati

, Ronia Tavasolian

, Sareh Shahdab

, Stephanie M. Tomlinson

Margarita Bobonis Babilonia

, Jeffrey Huang

, Danielle B. Tometich

, Kea Turner

Heather S.L. Jim

, Amir Alishahi Tabriz

University of South Florida Morsani College of Medicine, Tampa, FL, United States

College of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Department of Clinical Science and Nutrition, University of Chester, England

University of South Florida Health Libraries Morsani University of South Florida Morsani College of Medicine, Tampa, FL, United States

Supportive Care Medicine Department, Behavioral Medicine Services, Moftt Cancer Center, Tampa, FL, United States

Department of Psychiatry and Behavioral Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, United States

Department of Oncological Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, United States

Department of Anesthesiology, Moftt Cancer Center, Tampa, FL, United States

Department of Health Outcomes and Behavior, Moftt Cancer Center, Tampa, FL, United States

Department of Oncological Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, United States

ARTICLE INFO

Keywords:

Ketamine

Cancer

Depression

Antidepressant

Systematic review

ABSTRACT

Background: Management of depression in the oncology population includes supportive psychotherapeutic in-

terventions with or without psychotropic medication, which take time to demonstrate effectiveness. Fast-acting

interventions, like ketamine, can provide a rapid antidepressant effect; however, there has been limited research

on effects of ketamine among cancer patients. The objective of this review is to provide an overview of research

on the efcacy and safety of ketamine on depression in patients with cancer.

Methods: We reviewed the published literature in MEDLINE® (via PubMed®), EMBASE, and Scopus from 1

January 1982 to 20 October 2022. We screened the retrieved abstracts against inclusion criteria and conducted a

full-text review of eligible studies. Following extraction of data from included studies, we used a framework

analysis approach to summarize the evidence on using ketamine in patients with cancer.

Results: All 5 included studies were randomized clinical trials conducted in inpatient settings in China. In all

included studies ketamine was administered intravenously. Three studies used only racemic ketamine, and two

studies used both S-ketamine and racemic ketamine. All included studies reported ketamine a tolerable and

effective drug to control depression symptoms.

Conclusion: Included studies showed administration of sub-anesthesia ketamine signicantly improves post-

operative depression among patients with cancer.

Introduction

Patients with cancer experience an increased risk of depression and

suicide compared to the general population. (

Amiri & Behnezhad, 2020;

Du et al., 2020; Krebber et al., 2014; Lee et al., 2021; Walker et al., 2013)

Depression in patients with cancer can negatively impact acceptance

and adherence to oncological treatments, extend hospitalization, and

increase suicide risk and mortality. (

Colleoni et al., 2000; Pitman,

Suleman, Hyde & Hodgkiss, 2018

; Prieto et al., 2002; Tian, Chen &

Hang, 2009

; Yousaf, Christensen, Engholm & Storm, 2005) Depression is

also associated with greater postoperative pain, higher incidence of

postoperative infections, as well as poor health-related quality of life.

(

Alishahi Tabriz et al., 2023; Wang et al., 2020) Management of

depression in the oncology population is challenging because optimal

* Corresponding author at: 12902 USF Magnolia Drive, Tampa, FL 33612.

E-mail addresses:

[email protected] (L. Azari), [email protected] (S.M. Tomlinson), margarita.bobonis@moftt.org (M. Bobonis Babilonia), jeffrey.huang@

moftt.org

(J. Huang), danielle.tometich@moftt.org (D.B. Tometich), kea.turner@moftt.org (K. Turner), heather.jim@moftt.org (H.S.L. Jim), amir.alishahi@

moftt.org

(A.A. Tabriz).

Contents lists available at ScienceDirect

International Journal of Clinical and Health Psychology

journal homepage:

www.elsevier.es/ijchp

https://doi.org/10.1016/j.ijchp.2023.100428

Received 2 October 2023; Accepted 6 December 2023

International Journal of Clinical and Health Psychology 24 (2024) 100428

treatment includes a combination of psychotherapeutic interventions

with or without psychotropic medication (

Mehta & Roth, 2015), which

take time to demonstrate effectiveness. For example, supportive psy-

chotherapy interventions can take at least one month to reduce

depressive symptoms, and current antidepressants used to manage

depression require at least four to six weeks to show their clinical

benet. (

Rayner et al., 2010, 2011; Sanacora, Treccani & Popoli, 2012)

Providing a fast-acting clinical solution beyond therapeutic intervention

for patients with cancer could potentially alleviate added adverse out-

comes experienced by this population.

Ketamine, traditionally used as an anesthetic agent, provides a rapid

antidepressant effect that can last for one to two weeks after infusion.

(

Aan Het Rot, Zarate, Charney & Mathew, 2012; Corriger & Pickering,

2019

; McGirr et al., 2015) While ketamine has shown signicant im-

provements in clinician-rated measures of depressive severity symptoms

among the general population, (

McInnes, Qian, Gargeya, DeBattista &

Heifets, 2022

; Rosenblat et al., 2019; Wilkinson et al., 2018; Xiong et al.,

2021

) to our knowledge, studies evaluating the efcacy and safety of

ketamine in oncology population are limited. This is an important gap to

address because of comorbidities, life expectancy, and polypharmacy.

Patients with cancer often receive complicated medication regimens to

manage their conditions, primarily through oral administration, which

often results in signicant gastrointestinal symptoms such as nausea,

vomiting, diarrhea, constipation, and anorexia. (

Andreyev, Davidson,

Gillespie, Allum & Swarbrick, 2012

; Janelsins et al., 2013) Given the

lack of non-enteral formulations for most antidepressant medications,

there is a need for alternative formulations that can be administered

through routes such as intravenous and intranasal. Ketamine, which is

capable of being administered through various routes, including intra-

venous and intranasal, may potentially decrease side effects and

improve symptom burden. The clinical use of ketamine is rapidly

evolving, therefore reviewing the evidence available in the literature

regarding the efcacy and safety of ketamine for the treatment of

depression in the oncology population and identifying potential gaps for

future research is needed.

The objective of this systematic literature review is to provide an

overview of research on the efcacy and safety of ketamine on depres-

sion in patients with cancer. The results of this review can inform future

clinical applications of ketamine for depression in patients with cancer.

Methods

We conducted a systematic literature review according to Preferred

Reporting Items for Systematic Reviews and Meta-Analyses guidelines

(Appendix A). The study protocol was registered in the International

Prospective Register of Systematic Reviews (PROSPERO) (registration

number: CRD 42,022,340,316).

Study inclusion and exclusion criteria

To be included in the review, we required articles to assess the

relationship between using ketamine in adult patients with cancer and

depression. Additionally, articles were required to be written in the

English language, peer-reviewed, and report the results of an empirical

study. We excluded articles if the target population was children

(younger than 18), and those focused only on molecular aspects of ke-

tamine. A detailed list of inclusion and exclusion criteria can be found in

Appendix B.

Information sources and search strategy

In line with previous research, (Amir

Alishahi Tabriz et al., 2022) the

literature search strategy was developed by the rst author along with a

professional medical research librarian. The search was intentionally

broad to minimize the risk of overlooking potentially relevant studies.

The search strategy was developed for the concepts of cancer and

ketamine administration. The search strategies were created using a

combination of subject headings and keywords and were used to search

MEDLINE® (via PubMed®), EMBASE, and Scopus from 1 January 1982

to 20 October 2022 (40 years of data), when all searches were

completed. We also manually scanned the citations of included studies

for relevant articles and references from similar systematic reviews in

case they were missed during indexing. As we considered only

peer-reviewed published studies, gray literature was not included. We

applied the Cochrane human studies lter to exclude animal studies and

added a systematic review keyword and publication type lter to

exclude systematic review articles. The complete strategy for each of the

searches can be found in Appendix C.

Study selection process

Each title and abstract was screened against the eligibility criteria by

two researchers. Discrepancies were resolved through discussions be-

tween members of each pair and, when necessary, a third team member

reviewed the discrepancy until a consensus was reached. To ensure

inter-rater reliability of reviews, three iterations of sample reviews were

conducted with each person reviewing 30 articles until an average

agreement of 83 % was reached. The full-text articles were screened in

the same manner.

Study quality assessment

Two independent researchers assessed the quality of included studies

using the NIH Quality Assessment Tool for the controlled intervention

studies. ("Study Quality Assessment Tools,") We assigned quality of each

study as good, fair, or poor (see Appendix D). Disagreements in the risk

of bias scoring were resolved by consensus or by a discussion with a third

author.

Data extraction and analysis

We did not conduct a meta-analysis due to heterogeneity in pop-

ulations, heterogeneity in how depression was measured, and small

sample of the included studies. We used a framework analysis approach

to summarize the evidence on using ketamine in patients with cancer.

(Ritchie, Lewis, Lewis, Nicholls & Ormston, 2013) The framework

analysis approach included ve stages (i.e., familiarization, framework

selection, indexing, charting, and mapping and interpretation). First,

team members read included studies and familiarized themselves with

the literature. Second, we identied conceptual frameworks that served

as the codes for data abstraction. To describe studies in which re-

searchers have studied administering ketamine in patients with cancer,

we used a thematic framework that included publication year, design,

outcome(s), type of cancer, objective(s), country, setting, dosage, out-

comes, and the relationship between using the ketamine and outcomes.

We also collected data on the route of ketamine administration (e.g.,

infusion, intranasal), and the type of ketamine they used (e.g., S-keta-

mine (esketamine), R-ketamine (arketamine), R & S Ketamine (racemic

ketamine)). Next, pairs of authors completed indexing and charting by

placing selected text from included articles into the appropriate cells

within our framework. Data from the included studies were extracted

into a standardized data extraction form in Microsoft Excel (version

2016). Last, we analyzed extracted data from each cell to describe the

studies and ndings of using ketamine in patients with cancer.

Results

Study selection

The searches in PubMed, Embase, and Scopus yielded 1486 citations.

These citations were exported to Endnote (Version 20) and 33 duplicates

were removed using the Endnote deduplication feature. This resulted in

L. Azari et al.

International Journal of Clinical and Health Psychology 24 (2024) 100428

a total of 1453 unique citations found across all database searches. Titles

and abstracts of the 1453 articles were screened; 86 were selected for

full-text screening. Of the 86 studies, 81 were excluded at full-text

screening or during extraction attempts with the consensus of two co-

authors; 5 unique eligible studies were included (

Fig. 1).

Characteristics of included studies

The included studies were conducted between 2014 and 2018. (

Fan

et al., 2017

; Liu et al., 2021; Ren et al., 2022; J. Wang et al., 2020; Xu,

Zhan & Chen, 2017

) All the included studies were randomized clinical

trials and were conducted in inpatient settings (i.e., hospitals) in China.

All of the studies targeted surgical patients. The studies covered several

cancer types including two focused on breast cancer, (

Liu et al., 2021;

Xu et al., 2017) one on cervical cancer, (J. Wang et al., 2020) one on

colorectal cancer, (Ren et al., 2022) and one study focused on more than

one cancer type. (

Fan et al., 2017) Characteristics of included studies are

shown in

Table 1.

Quality assessment of studies

The quality of all of the included studies was good (assessed by NIH

Quality Assessment Tool for the controlled intervention studies). (

Study

Quality Assessment Tools

) The details of the quality assessment of the

included studies are shown in Appendix D.

Ketamine administration characteristics

In all included studies, ketamine was administered intravenously.

Three studies used only racemic ketamine (i.e., racemic ketamine

Fig. 1. PRISMA Literature Flow Diagram.

L. Azari et al.

International Journal of Clinical and Health Psychology 24 (2024) 100428

hydrochloride), (

Fan et al., 2017; Ren et al., 2022; Xu et al., 2017) and

two studies used both S-ketamine and racemic ketamine (both reported

that S-ketamine is more effective than racemic ketamine for reducing

postoperative depression). (

Liu et al., 2021; J. Wang et al., 2020) The

dosage of ketamine ranged from 0.1 mg per kg to 0.5 mg per kg. The

details of ketamine administration can be found in

Table 2.

Outcome measurement

As shown in

Table 3, three of included studies used the Hamilton

Rating Scale for Depression (HAMD-17), (Liu et al., 2021; J. Wang et al.,

2020; Xu et al., 2017) one study measured suicidal ideation using the

Beck Scale for Suicidal Ideation (BSI) score and the suicidal section of

the Montgomery-Asberg Depression Rating Scale (MADRS-SI), (

Fan

et al., 2017

) and one study measured anxiety and depression using the

Hospital Anxiety and Depression Scale (HADS). (

Ren et al., 2022) All

included studies conducted assessments multiple times, and the assess-

ment time points ranged from one day before the operation to three

months after the surgery. As a secondary outcome, four studies

measured pain (using Visual Analog Scale (VAS)), (

Liu et al., 2021; Ren

et al., 2022

; J. Wang et al., 2020; Xu et al., 2017) one study measured

social support (

Xu et al., 2017), one study measured the quality of

post-operation recovery (using Quality of Recovery-40 (QoR-40) ques-

tionnaire), (

Ren et al., 2022) two studies measured serum levels of BDNF

and 5-HT, (

Liu et al., 2021; J. Wang et al., 2020) and one study measured

inammatory response (e.g., IL-6, IL-8, and TNF-

levels). (Ren et al.,

Table 1

Characteristic of included studies.

Citation Participants (N) Setting Recruitment

Period

Inclusion/Exclusions criteria

Fan et al.

(2017) (1)

Patients with lung (7), gastric

(12), bone (7), and pancreas

cancer (11)

Huai’an First People’s Hospital and

Maternal & Child Health Care

Hospital of Huai’an City

February 2011 to

May 2016

Inclusion criteria: between 18 and 70 years old; rst diagnosed as

cancer within 3 months; and basic communication capability to

complete the interview.

Exclusion criteria: diagnosed with cardiorespiratory diseases; drug

addiction history or sedative–hypnotic drug(s) use; neuropsychiatric

or cognitive diseases or a related treatment history; suicidal attempts

or ideation before cancer diagnosis; and family history of psychiatric

history

Liu et al.

(2021) (2)

Patients with breast cancer

(303)

Fengcheng Hospital June 2017 to

June 2018

Inclusion criteria: HAMD-17 8–24 score, and American Society of

Anesthesiologists (ASA) score I-II before surgery

Exclusion criteria: HAMD score less than or equal to 7 or greater than

or equal to 24 before the study, psychiatric disorders such as mania

and schizophrenia, and severe liver, renal, cardiovascular, or

systematic inammatory diseases.

Ren et al.

(2022) (3)

Patients with colorectal

cancer (104)

Gongli hospital Jan 2015 to

October 2017

Inclusion criteria: American Society of Anesthesiologists (ASA) class

I–II identication undergoing elective colorectal cancer surgery

under general anesthesia for less than 4 h, the incision expected to be

more than 10 cm, age between 40 and 70 years with the body mass

index (BMI) ranging from 18 to 24 kg m

Exclusion criteria: poor understanding and mental or central nervous

system disorders before operation, presence of diabetes and heart

disease, hormone therapy during operation, those with ketamine or

opioid allergy, presence of severe liver and kidney dysfunction,

alcohol addiction or frequent use of sedative and analgesic drugs.

Wang et al.

(2020) (4)

Patients with cervical

carcinoma (417)

Hospital of Shanghai University April 2015 to

July 2018

Inclusion criteria: Hamilton Rating Scale for Depression scores within

8–24, and American Society of Anesthesiologists score of I-II.

Exclusion criteria: Having mental diseases or psychiatric history such

as schizophrenia and mania, receiving psychotropic substances,

having severe system diseases such as heart, renal and liver diseases.

Xu et al.

(2017) (5)

Patients with breast cancer

(50)

Hospital of Nanchang University May 2014 to

March 2015

Inclusion criteria: underwent modied radical mastectomy of

unilateral breast cancer, age between 30 and 55 years old, have ≥ 5

years of education, American Society of Anesthesiologists I-II grade,

HAMD score ≥ 17 points, were married and generational, mainly by

the immediate family care after surgery.

Exclusion criteria: antidepressant treatment within 2 months,

preoperative radiotherapy and chemotherapy treatment, previous

personality disorder, mental retardation, brain damage or brain

disease, combined with schizophrenia, mania and other mental

illness, hyperthyroidism or hypothyroidism, severe cardiovascular

disease, diabetes, severe anemia, and heart, lung, liver, kidney

function abnormalities, immune system diseases, or the use of drugs

affecting the immune system obviously, pregnancy or lactation, a

history of illicit drug use (such as marijuana, ecstasy, etc.),

participation in other clinical trials, refused to participate.

1. Fan W, Yang H, Sun Y, Zhang J, Li G, Zheng Y, et al. Ketamine rapidly relieves acute suicidal ideation in cancer patients: a randomized controlled clinical trial.

Oncotarget. 2017;8(2):2356.

2. Liu P, Li P, Li Q, Yan H, Shi X, Liu C, et al. Effect of Pretreatment of S-Ketamine On Postoperative Depression for Breast Cancer Patients. Journal of Investigative

Surgery. 2021;34(8):883–8.

3. Ren Q, Hua L, Zhou X, Cheng Y, Lu M, Zhang C, et al. Effects of a Single Sub-Anesthetic Dose of Ketamine on Postoperative Emotional Responses and Inammatory

Factors in Colorectal Cancer Patients. Frontiers in Pharmacology. 2022;13.

4. Wang J, Wang Y, Xu X, Peng S, Xu F, Liu P. Use of various doses of S-ketamine in treatment of depression and pain in cervical carcinoma patients with mild/moderate

depression after laparoscopic total hysterectomy. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2020;26:e922028–1.

5. Xu R, Zhan Y, Chen S. Effect of intraoperative single administration of sub-anesthesia ketamine on breast cancer patients with depression. BIOMEDICAL RESEARCH-

INDIA. 2017;28.

All the included studies were randomized clinical trials and were conducted in China.

L. Azari et al.

International Journal of Clinical and Health Psychology 24 (2024) 100428

2022) None of the included studies measured comorbid psychotropic

medication use (i.e., if ketamine administration changed the medication

use among the patients).

Efcacy and safety of ketamine

All included studies reported intraoperative single dose ketamine has

a rapid antidepressant effect on cancer patients (one day after surgery),

but that effect decreases along with time. Four of ve included studies

reported three days as the duration of ketamine efcacy, (

Fan et al.,

2017

; Ren et al., 2022; J. Wang et al., 2020; Xu et al., 2017) and one

study claimed it lasted for a month. (

Liu et al., 2021) One study showed

the BDNF and 5-HT levels were negatively correlated with the HAMD-17

score, and one study showed a single sub-anesthetic dose of ketamine

can reduce the levels of IL-6, IL-8, and TNF-

. (Ren et al., 2022) None of

the included studies reported a signicant difference in the incidence of

adverse events. (

Table 4)

Discussion

We conducted this review to summarize the literature about the ef-

cacy and safety of ketamine on depression in patients with cancer.

Patients with cancer are at greater risk for depression than the general

population and experience negative outcomes as a result of depression

(e.g., extended hospitalization, increased postoperative pain and in-

fections, and increased suicide risk and mortality) (

Block, 2000; Breit-

bart et al., 2000

; Chachamovich, Fleck, Laidlaw & Power, 2008;

Chongpison et al., 2016; Salibasic & Delibegovic, 2018; Y. H. Wang

et al., 2020

). Despite the severity, our systematic review demonstrates

that there have been limited studies evaluating ketamine as a treatment

for depression among cancer patients. We only identied ve studies (all

were conducted in China) that investigate the effects of ketamine on

depression among patients with cancer. This nding highlights a need

for conducting more robust trials to evaluate safety and efcacy of ke-

tamine on depressive symptoms in patients with cancer.

Our ndings showed that ketamine is a safe (no signicant adverse

events reported) and effective drug to control depression symptoms and

correlated symptoms, such as pain. Included studies showed that an

intraoperative single administration of sub-anesthesia ketamine signif-

icantly improves postoperative depression among patients with cancer.

However, included studies showed that the efcacy of ketamine rapidly

declined over time. These ndings highlight the need for studies that

assess the effects of longitudinal usage of ketamine on depression among

oncology population. For example, the “S” enantiomer of ketamine

(known as esketamine) was approved by the FDA in 2019 as a nasal

spray for treatment-resistant depression in adults in conjunction with

oral antidepressants. (

Bahr, Lopez & Rey, 2019) Future studies may

assess continuous esketamine usage in the long-term management of

Table 2

Characteristics of Ketamine usage.

Citation Type of

Ketamine

Route of

administration

Dosage (including

duration)

How

long the

effects

lasted

Fan et al.

(2017)

(1)

Racemic

ketamine

hydrochloride

Intravenous • Ketamine group:

0.5 mg/kg

racemic

ketamine over

40 min

• Control group:

0.05 mg/kg

midazolam over

40 min

First

three

days

after

surgery

Liu et al.

(2021)

(2)

Racemic

ketamine and

S-ketamine

Intravenous • Control group: 2

ml of normal

saline after

analgesia

induction

• Racemic

ketamine group:

2 ml of 0.125

mg/kg of

racemic

ketamine after

analgesia

induction

• S-ketamine

group: 2 ml of

0.125 mg/kg of

S-ketamine after

analgesia

induction

One

month

Ren

et al.

(2022)

(3)

Ketamine Intravenous • Ketamine group

1: 0.1 mg/kg 5

min before

operation

• Ketamine group

2: 0.2 mg/kg 5

min before

operation

• Ketamine group

3: 0.3 mg/kg 5

min before

operation

• Control group:

normal saline 5

min before

operation

First

three

days

after

surgery

Wang

et al.

(2020)

(4)

Racemic

ketamine and

S-ketamine

Intravenous • 50 ml 0.5 mg/kg

racemic

ketamine 1 h

after the start of

anesthesia

• 50 ml 0.5 mg/kg

S-ketamine 1 h

after the start of

anesthesia

• 50 ml 0.25 mg/

kg S-ketamine 1

h after the start

of anesthesia

• Control group:

50 ml normal

saline 1 h after

the start of

anesthesia

First

three

days

after

surgery

Xu et al.

(2017)

(5)

Ketamine

hydrochloride

Intravenous • Ketamine group:

0.5 mg/kg

ketamine 1 h

after the start of

anesthesia

• Control group:

50 ml of isotonic

saline 10 min

after the start of

anesthesia

First

three

days

after

surgery

1. Fan W, Yang H, Sun Y, Zhang J, Li G, Zheng Y, et al. Ketamine rapidly relieves

acute suicidal ideation in cancer patients: a randomized controlled clinical trial.

Oncotarget. 2017;8(2):2356.

2. Liu P, Li P, Li Q, Yan H, Shi X, Liu C, et al. Effect of Pretreatment of S-Ketamine

On Postoperative Depression for Breast Cancer Patients. Journal of Investigative

Surgery. 2021;34(8):883–8.

3. Ren Q, Hua L, Zhou X, Cheng Y, Lu M, Zhang C, et al. Effects of a Single Sub-

Anesthetic Dose of Ketamine on Postoperative Emotional Responses and In-

ammatory Factors in Colorectal Cancer Patients. Frontiers in Pharmacology.

2022;13.

4. Wang J, Wang Y, Xu X, Peng S, Xu F, Liu P. Use of various doses of S-ketamine

in treatment of depression and pain in cervical carcinoma patients with mild/

moderate depression after laparoscopic total hysterectomy. Medical Science

Monitor: International Medical Journal of Experimental and Clinical Research.

2020;26:e922028–1.

5. Xu R, Zhan Y, Chen S. Effect of intraoperative single administration of sub-

anesthesia ketamine on breast cancer patients with depression. BIOMEDICAL

RESEARCH-INDIA. 2017;28.

L. Azari et al.

International Journal of Clinical and Health Psychology 24 (2024) 100428

depressive symptoms in patients with cancer.

We found that three of the ve included studies compared different

types and dosages of ketamine. (

Liu et al., 2021; Ren et al., 2022; J.

Wang et al., 2020) They showed S-ketamine is more effective than

racemic ketamine for reducing postoperative depression, (

Liu et al.,

2021; J. Wang et al., 2020) and higher doses of ketamine (e.g., 0.5

mg/kg vs 0.25 mg/kg) (J.

Wang et al., 2020) had better efcacy in

reducing depression. This implies that, instead of ketamine hydrochlo-

ride, 0.5 mg/kg (diluted in 0.9 % saline, over 40 min by intravenous

pump) of S-ketamine is a more effective choice for management of

depression in patients with cancer.

Interestingly, while the participants of four of the ve included

studies were moderate to severely depressed, (

Fan et al., 2017; Liu et al.,

2021

; J. Wang et al., 2020; Xu et al., 2017) none of the included studies

assessed suicidality or comorbid psychotropic medication use (e.g., any

changes in the type and/or dose of antidepressants after ketamine

administration). Future studies are needed to assess the impact of ke-

tamine administration on the usage of other psychotropic medications in

patients with cancer. Additionally, given that cancer patients are at

increased risk for suicide, (

Fang et al., 2012; Henson et al., 2019;

Misono, Weiss, Fann, Redman & Yueh, 2008; Ravaioli et al., 2020;

Zaorsky et al., 2019) future studies should assess the effects of ketamine

on suicidal ideation among cancer patients.

This review has some limitations. First, our goal was to assess the

efcacy and safety of ketamine for treatment of depression among

cancer patients; therefore, we excluded studies that only focused on

biological aspects of ketamine that may have provided the molecular

pathway that explains the relationship between ketamine and depres-

sion. Second, we limited our systematic reviews to English-only articles

which could result in missing papers published in other languages.

Conclusion

Despite the ample evidence for treatment of depression in general

population, the antidepressant effect of ketamine in the cancer popu-

lation remains understudied. Current literature shows that administra-

tion of intraoperative single-dose of ketamine signicantly improves

postoperative depression among patients with cancer, however, the ef-

cacy of ketamine declined over time. Future studies are needed to

examine ketamine use as a treatment for depression among cancer pa-

tients and to assess how longitudinal use of ketamine affects the duration

of treatment efcacy.

Consent for publication

Our manuscript does not contain any identiable individual-level

Table 3

. Included studies outcomes, how and when they measured.

Citation Main outcome Secondary outcome(s) Adverse effects Assessment Time-

points

Fan et al.

(2017)

(1)

Suicidal ideation measured by the Beck

Scale for Suicidal Ideation (BSI) score

and suicidal section of the Montgomery-

Asberg Depression Rating Scale

(MADRS-SI).

• Depression severity measured by MADRS

score

Not mentioned One, three and seven

days after operation

Liu et al.

(2021)

(2)

Depression measured by Hamilton

Rating Scale for Depression (HAMD-17).

• Pain status measured by Visual Analog Scale

• Serum levels of BDNF and 5-HT was

measured by ELISA

• Operation time, bleeding volume, and

complication rate.

Neither S-ketamine nor racemic ketamine

signicantly changed the operation time,

bleeding volume and complication.

Three days, one week,

one month and three

months after surgery.

Ren et al.

(2022)

(3)

Anxiety and depression measured by

Hospital Anxiety and Depression Scale.

• The quality of postoperative recovery

measured by Quality of Recovery-40 (QoR-

40) questionnaire

• The levels of IL-6, IL-8, and TNF-

measured

by ELISA

• Pain measured by Visual Analogue Score

(VAS)

• Sedation measured by Ramsay Sedation

score

• Adverse reactions and post-operative com-

plications (cough during extubating,

delirium during recovery, sedation within

30 min after extubating, dizziness, nausea,

vomiting, diplopia, hallucination, and other

adverse reactions)

There were no signicant differences in

extubation time, postoperative cough,

emergence agitation or delirium among the

four groups. No dizziness, nausea, vomiting,

diplopia, or other adverse reactions were

found 30 min after extubation.

One, two and three

days after operation

Wang

et al.

(2020)

(4)

Depression measured by Hamilton

Rating Scale for Depression (HAMD-17).

• Pain measured by Visual Analogue Score

(VAS)

• BDNF and 5-HT levels measured by ELISA

No signicant difference was observed in

operative time, bleeding volume,

hospitalization time, or 1-month

complication rate

One, two, three, ve

and seven days after

operation

Xu et al.

(2017)

(5)

Depression measured by Hamilton

Rating Scale for Depression (HAMD-17).

• Pain status measured by Visual Analogue

Scale/Score (VAS)

• The Social Support Scale (SSRS)

• Extubating time

There was no signicant difference in the

incidence of adverse reactions and duration

of extubation between the two groups.

One day before

operation and one,

three and seven days

after operation

1. Fan W, Yang H, Sun Y, Zhang J, Li G, Zheng Y, et al. Ketamine rapidly relieves acute suicidal ideation in cancer patients: a randomized controlled clinical trial.

Oncotarget. 2017;8(2):2356.

2. Liu P, Li P, Li Q, Yan H, Shi X, Liu C, et al. Effect of Pretreatment of S-Ketamine On Postoperative Depression for Breast Cancer Patients. Journal of Investigative

Surgery. 2021;34(8):883–8.

3. Ren Q, Hua L, Zhou X, Cheng Y, Lu M, Zhang C, et al. Effects of a Single Sub-Anesthetic Dose of Ketamine on Postoperative Emotional Responses and Inammatory

Factors in Colorectal Cancer Patients. Frontiers in Pharmacology. 2022;13.

4. Wang J, Wang Y, Xu X, Peng S, Xu F, Liu P. Use of various doses of S-ketamine in treatment of depression and pain in cervical carcinoma patients with mild/moderate

depression after laparoscopic total hysterectomy. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2020;26:e922028–1.

5. Xu R, Zhan Y, Chen S. Effect of intraoperative single administration of sub-anesthesia ketamine on breast cancer patients with depression. BIOMEDICAL RESEARCH-

INDIA. 2017;28.

L. Azari et al.

International Journal of Clinical and Health Psychology 24 (2024) 100428

(patient or clinician) data in any form. We obtained informed consent

before each interview.

Availability of data and material

The data used and/or analyzed during the current study are available

from the corresponding author on reasonable request and subject to IRB

guidelines.

Declaration of Competing Interest

The authors declare that they have no competing interests.

Funding

Leila Azari was supported by the Research, Innovation, & Scholarly

Endeavors (RISE) Ofce at USF Health, Morsani College of Medicine.

The RISE ofce had no role in the study design, collection, analysis, or

interpretation of the data, writing the manuscript, or the decision to

submit the paper for publication.

Acknowledgment

Not applicable.

Supplementary materials

Supplementary material associated with this article can be found, in

the online version, at

doi:10.1016/j.ijchp.2023.100428.

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Table 4

. Objective(s), and conclusion(s) of included studies. .

Citation Study objective(s) Study conclusion

Fan et al.

(2017)

(1)

To examine the rapid

antidepressant effects of single

dose ketamine on suicidal

ideation and overall depression

level in patients with newly

diagnosed cancer.

• Ketamine has antidepressant

and anti-suicidal effects that

were seen as soon as 1 day

following administration and

typically lasted for at least 3

days

• Ketamine is safe and effective

for short term use at a sub-

anesthetic dose of 0.5 mg/kg

over 40 min.

Liu et al.

(2021)

(2)

To investigate the effect of the

pretreatment of S-ketamine on

postoperative depression for

breast cancer patients with

mild/moderate depression.

• S-ketamine is more effective

than racemic ketamine for

reducing postoperative

depression and pain for breast

cancer patients.

• The BDNF and 5-HT levels were

negatively correlated with the

HAMD-17 score.

Ren at al.

(2020)

(3)

To investigate the effect of a

single sub-anesthetic dose of

ketamine on postoperative

anxiety, depression, and

inammatory factors in patients

with colorectal cancer.

• A single sub-anesthetic dose

(0.3 mg kg-1) of ketamine can

signicantly improve the post-

operative anxiety and depres-

sion of colorectal cancer

patients and reduce the levels

of IL-6, IL-8, and TNF-

Wang et al.

(2020)

(4)

To investigate the effects of

various doses of S-ketamine on

depression and pain

management of cervical

carcinoma patients with mild/

moderate depression.

• A subanesthetic dose of S-

ketamine had better effects on

pain and depression than

racemic ketamine in cervical

carcinoma patients with mild/

moderate depression.

• High-dose S-ketamine had

better efcacy in reducing

short-term depression

compared with the same dose

of racemic ketamine.

Xu et al.

(2017)

(5)

To observe the effect of single

administration of sub -

anesthesia ketamine on breast

cancer patients with depression.

Intraoperative single

administration of sub-anesthesia

ketamine has a signicant effect

on postoperative breast cancer

patients with depression, but that

effect may decrease along with

the time.

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