Effectiveness and Safety of Ketamine for Unipolar Depression: a Systematic Review

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Behavioral Health Articles Behavioral Health Services / Psychiatry

8-27-2020

Effectiveness and Safety of Ketamine for Unipolar Depression: a Effectiveness and Safety of Ketamine for Unipolar Depression: a

Systematic Review Systematic Review

Raheel I. Memon

Henry Ford Health

, [email protected]

Sadiq Naveed

Amber Ehsan Faquih

Ania Fida

Noureen Abbas

See next page for additional authors

Follow this and additional works at: https://scholarlycommons.henryford.com/behavioralhealth_articles

Recommended Citation Recommended Citation

Memon RI, Naveed S, Faquih AE, Fida A, Abbas N, Chaudhary AMD, and Qayyum Z. Effectiveness and

Safety of Ketamine for Unipolar Depression: a Systematic Review. Psychiatr Q 2020.

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Authors Authors

Raheel I. Memon, Sadiq Naveed, Amber Ehsan Faquih, Ania Fida, Noureen Abbas, Amna Mohyud Din

Chaudhary, and Zheala Qayyum

This article is available at Henry Ford Health Scholarly Commons: https://scholarlycommons.henryford.com/

behavioralhealth_articles/83

REVIEW ARTICLE

Effectiveness and Safety of Ketamine for Unipolar

Depression: a Systematic Review

Raheel Imtiaz Memon

& Sadiq Naveed

& Amber Ehsan Faquih

& Ania Fida

Noureen Abbas

& Amna Mohyud Din Chaudhary

& Zheala Qayyum

Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract

Major Depressive Disorder (MDD) is a common psychiatric disorder with major impli-

cations for healthcare system and socioeconomic burden. For chronic and treatment-

resistant depression, Ketamine has emerged as a possible treatment option. This system-

atic review explores the evidence for the effectiveness and tolerability of Ketamine in

patients with MDD. This systematic review was conducted following the guidelines of

Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) check-

list. Eight electronic databases were searched by using search terms: (ketamine) AND

(trial OR RCT OR clinical-trial) AND (depressive OR depression OR “depressive-

disorder” ). After a rigorous screening process against the predetermined eligibility

criteria, 35 randomized controlled trials (RCTs) were included. Quality assessment of

included studies was done by using the Cochrane risk-of-bias tool for RCTs. Thirty-five

RCTs are included in this review article with majority of studies from United States, Iran,

and China. Intravenous (IV) Ketamine was effective in 70% (21/30) of the included

studies whereas oral and Intranasal (IN) Ketamine were effective in two and three studies,

respectively. The majority of studies (6/8) using Ketamine as anesthetic agent during

electroconvulsive therapy (ECT) failed to show an improvement compared to the partic-

ipants receiving ECT and placebo. The most common reported side effects were nausea,

vomiting, dizziness, diplopia, drowsiness, dysphoria, hallucinations, and confusion. Ke-

tamine is an effective treatment option for patients with MDD with undesirable effects

when administered via oral, IV and IN routes. Ketamine agumentation of ECT requires

further exploration in well-designed studies with adequate sample size. The short-lived

antidepressant effect of Ketamine is a potential limitation, therefore, further studies

administering multiple infusions for acute treatment and maintenance are necessary.

Keywords Ketamine

MDD

Major depressivedisorder

MDD

Treatment-resistant depression

Psychiatric Quarterly

https://doi.org/10.1007/s11126-020-09830-6

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11126-020-

09830-6) contains supplementary material, which is available to authorized users.

* Sadiq Naveed

naveed193@gmail.com

Extended author information available on the last page of the article

Introduction

Major Depressive Disorder (MDD) is a widespread and disabling illness with a lifetime

prevalence of 20% in USA. MDD affects around 264 million people throughout the world,

leading to major health system and socioeconomic burden [1,2]. The global incidence of

depression has increased by 49.86% in the last two decades and it is estimated that MDD will

become the leading cause of debility by the year 2030 [3]. Untreated depression has debili-

tating consequences for individuals, resulting in academic, interpersonal, social, and occupa-

tional impairments [4]. The clinical course of depression tends to be chronic with a high rate of

recurrence of around 80% [4]. The economic burden of depression is reported to be around

$210.5 billion with approximately 45% due to direct costs, 5% to suicide-related costs, and

50% to workplace costs [5]. Beside the financial implications, around 90% of suicidal patients

have an underlying psychiatric illness with MDD being the top of the list [6]andabout2–15%

of patients with MDD complete suicide [7].

The treatment of depression requires several careful considerations, such as MDD with

suicidal behaviors, early-onset depression, chronic depression, and treatment- resistant depres-

sion. With an increased emphasis on deinstitutionalization, there is a policy shift to manage

patients in a less restrictive environment with shortened length of hospital stays [8]. In this

context, pharmacological options with robust and faster response became critically important

in treatment of patients with MDD. Existing treatment options such as antidepressants,

psychotherapy, and electroconvulsive therapy (ECT) are effective but come at the cost of time

lag, so a large number of patients face the challenge of suicidal thoughts and impairing

depressive symptoms for weeks after initiation of treatment [9].

More importantly, treatment- resistant depression (TRD) continues to be a significant

public health issue. Despite multiple treatment regimens, about 60–70% of patients with

MDD respond to first-line antidepressants, whereas about one-third of patients struggle with

debilitating and chronic depression [2]. Recently, in addition to psychopharmacological

treatments mediated through monoamines, the glutamate pathway and N-methyl-D-aspartate

(NMDA) receptor antagonism have become the subject of attention.

Glutamate, a neurotransmitter associated with neuroplasticity and excitotoxicity action, has

antidepressant effect by its effect on different receptors, especially N-methyl-D-aspartate

(NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors.

Ketamine, a phencyclidine hydrochloride derivative and a non-competitive NMDA receptor

antagonist, was first approved in 1970 for anesthesia. It is also used during ECT since it can

intrinsically increase the seizure duration with minimal cognitive deficits [2,10,11]. The use of

Ketamine has recently expanded to its antidepressant use at s ub-anesthetic and sub-

dissociative doses, but the exact antidepressant mechanism is still unclear [12,13].

Ketamine’s NMDA receptor antagonism and facilitated AMPA receptor-mediated trans-

mission [14] result in a cascade of events, such as activation of the target of rapamycin

(mTOR) intracellular cascade and, specifically, upregulation of brain-derived neurotrophic

factor (BDNF). BDNF, a neurotrophic factor, is involved in neuro nal maturation,

neurogenesis, and synaptic plasticity [15]. Ketamine is a racemate compound of 2 enantio-

mers: R-(2)-ketamine e nantiomer (arketamine) and the S-(1)-ketamine enantiomer

(esketamine) which has about 3–4 folds higher affinity for NMDA receptor than arketamine

[16,17]. The half-life (t1/2) of Ketamine is reported to be around 3–4 h, but its antidepressant

action is reported to last for a week. This raises an important cue that its action is not entirely

dependent on NMDA receptors blockade but also has a long-term neuroprotective effect [18].

Psychiatric Quarterly

This systematic review provides a comprehensive overview of the use of Ketamine in the

prevention and treatment of unipolar depression.

Methods

This systematic review was conducted according to the guidelines of the Preferred Reporting

Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist (Supplementary

Table 1). The protocol was developed in March 2019 and was registered with the International

Prospective Register of Systematic Reviews (PROSPERO) in April 2019

(CRD42019125801).

Eligibility Criteria

The inclusion criteria were:

1. Randomized controlled trials (RCTs) focused on the treatment of unipolar depression with

ketamine as a pharmacotherapy.

2. RCTs that focused on the adult population with MDD were included, who were either

screened for depression using validated screening instruments or diagnostic systems (such

as International Statistical Classification of Diseases and Related Health Problems or

Diagnostic and Statistical Manual).

– No restriction on race, geography, sex, age, ethnicity, or language and publication

date were applied.

The exclusion criteria were:

1. Study design other than RCT (observational study, case reports, case series, letter to

editors, study protocols, thesis, reviews, commentary, conference papers, book chapter or

news articles).

2. Studies discussing the role of Ketamine for bipolar depression or diagnosis other than

MDD.

3. Overlapped data sets, unreliable information, and abstract-only articles.

4. In-vitro studies or animal studies.

Search Strategy

Eight academic databases were searched including PubMed, CINAHL, Cochrane

clinical trials registry, Web of Science, PsycINFO, POPLINE, Global Health Library,

and Virtual Health Library through September 2018, using the following search

strategy: (ketamine) AND (trial OR RCT OR Clinical-trial) AND (depressive OR

depression OR “d epressive-disorder”). The manual search of references and relevant

articles for included studies was performed by two independent reviewers. Any

discrepancies among reviewers were resolved by discussion or guidance f rom a senior

reviewer (SN).

Psychiatric Quarterly

Study Selection

Search results from the eight databases were imported to Endnote ×7 (Thompson Reuter, CA,

USA) to remove any duplicates. Two independent reviewers performed title and abstract

screening (when available) followed by the full-text screening of the included articles by using

the predetermined eligibility criteria. Disagreements were resolved by discussion among

reviewers or guidance from a senior reviewer (SN).

Data Extraction

The data were e xtracted by two independent reviewers and c ross-checked for accuracy by

the senior author (SN). The name of authors, sample size, site of the trial, participant

characteristics, route of administration, dose range, clinical outcomes, the adjunct treat-

ment used, and common side effects were tabulated. The meta-analysis was not performed

due to varying study d esign, population of interest, and treatment outcomes, posing

potential heterogeneity.

Risk of Bias Assessment

Two authors assessed the quality of the studies without blinding to authorship or journal, using

the Cochrane tool for randomized controlled trials against several matrices: a) sequence

generation, b) allocation concealment, c) blinding of participants and personnel, d) blinding

of outcome assessment, e) incomplete outcome data, f) selective reporting, and g) other bias.

Funding Source

There was no funding source for this study.

Results

Study Search

The initial search of databases revealed a total number of 689 non-duplicate references

predicated on their titles and abstracts screening. After the application of inclusion and

exclusion criteria, 581 citations were excluded after title and abstract screening. Later thorough

screening of 108 full texts eventually yielded 35 RCTs. Fig. 1,PRISMAFlowDiagram

summarizes the screening process.

Study Characteristics

This review article includes 35 RCTs conducted between 2002 to 2018, with most of the study

sites in the USA [14], Iran [9], and China (4) [19–23]. The remaining trials were singularly

conducted in Canada, UK, Taiwan, Australia, Japan, Scotland, and Czech Republic. Daly et al.

(2017) conducted one study in USA and Belgium [1] whereas Singh et al. conducted one study

in Belgium, Germany, and Poland. There were 2183 participants in these studies with an age

range of 18–80, however age range was not mentioned in two studies [24,25]. Most studies

Psychiatric Quarterly

included both men and women, except for two studies that were conducted exclusively in

women [18,26]. Tables 1 and 2 provides a summary of participant characteristics, character-

istics related to Ketamine, outcome measures, and side effects.

Fig. 1 PRISMA Flow Diagram

Psychiatric Quarterly

Table 1 Overview of randomized controlled trials included in the meta-analysis

Study Design Inclusion Criteria Primary Outcome Secondary Outcome

Alizadeh et al.,

2015

Propofol & Ketamine vs Propofol

&placebo

Age 18–65, suffering from MDD, and

HDRS score of ≥20

Mean HDRS scores Not mentioned

Arabzadeh et al.,

2018

Sertraline & Ketamine vs Sertraline

&placebo

Age 18–60, patients with moderate to

severe depression, HDRS

score ≥ 20

Change in the HDRS score from

baseline to week 2 across the two

groups.

1) Difference in the HDRS score at week 4

and 6.

2) Difference in early improvement (≥

20% reduction in HDRS score within

the first two weeks)

3) Response to treatment (≥50% reduction

in the HDRS score at the termination of

the trial)

4) Remission (HDRS score ≤ 7atthe

termina t io n of the tria l) between the two

groups.

Burger et al., 2016 Single infusion of Ketamine vs

placebo

Age 18–65 years, Beck Suicidality

Scale (BSS) score > 4, Beck Hope-

lessness Scale (BHS) score > 8,

Beck Depression Inventory score >

19, and the ability to give informed

consent. Negative pre gnan cy test

for females.

Beck Suicidality Scale (BSS) Beck Hopeless-ness Scale (BHS)

Canuso et al.,

2018

Esketamine vs Placebo Age 19–6 4, suffering from MD D

without psychotic features, and a

score >/=22 on the

Montgomery-Åsberg Depression

Rating Scale (MADRS).

1) Change in Montgomery-Åsberg

Depression Rating Scale (MADRS)

score from baseline to 4 h after

initial dose.

2) Clinician global judgment of suicide

risk (from the Suicide Ideation and

Behavior Assessment Tool).

The primary outco me measures at 24 h

and double-blind endpoint at day 25.

Carspecken et al.,

2018

Ketamine vs Methohexital All vetera ns >18 years of age,

scheduled for an index course of

ECT for TRD

PHQ-9, HAM-D MOCA

Chen et al., 2017 Ketamine vs propofol Age 18–65, with MDD, HAM-D,

scores >35.

Long-term memory, short-term

memory, and immediate memory

were assessed for all patients using

Depression was assessed by the 24-item

HAM-D interview

Psychiatric Quarterly

Table 1 (continued)

Study Design Inclusion Criteria Primary Outcome Secondary Outcome

the Wechsler Memory

Scale-Chinese Revision (WM S-RC)

Fan et al., 2017 Ketamine vs Midazolam Participants with MDD and newly

diagnosed breast cancer

(A) Suicidal ideation severity

evaluated with BSI score.

(B) Suicidal ideation severity

evaluated with MADRS-SI

Score.

evaluated with MADRS score

Not mentioned

Gamble et al.,

2018

Ketamine vs Propofol Age > 17, TRD, MADRS score of 20. Number of ECT treatments required to

reach a 50% reduction in baseline

MADRS

1. Change in CADSS

2. Change in ALS-18

3. Change in ECT energy settings and

seizure quality

4. Hemodynamic instab ility and

respiratory complications

5. Time to discharge

6. Change in MADRS score 24 h after

each treatment and 30 days after final

treatment for an expected average of

2 months

7. The number of ECT sessions required to

achieve depression remission (MADRS

≤10)

8. The proportion of depressed patients

(MADRS >20) at 30 days after the last

ECT session

9. Change in systolic blood pressure

Ghasemi et al.,

2013

Ketamine vs ECT Participants with MDD, ages

18–75 years, with a current major

depressive episode.

HDRS, BDI at baseline, 24 h after

each treatment, 72 h and one week

after the last (third)

Ketamine or ECT.

Not mentioned

Haile et al., 2013 Ketamine vs Midazolam Age 21–80 years, participants with

TRD, current episode of depression.

Not mentioned

Psychiatric Quarterly

Table 1 (continued)

Study Design Inclusion Criteria Primary Outcome Secondary Outcome

Response = 50% or greater reduction

in MADRS score compa red to

baseline at 7 day post-infusion

Hu et al., 2015 Ketamine vs Placebo Age 18–6 0 years, patients with TRD,

≥ 24 on HAM-D

Response = ≥ 50% reduction in

baseline MADRS scores.

Remission = MADRS total score ≤ 10

- Proportion of responders and remitters in

each group

- Severity of investigator-rated depressive

symptoms (MADRS)

- Self-rated scores on Quick Inventory of

Depressive Symptomatology –

Self-Report (QIDS-SR) – Chinese

version,

- Suicidal ideation (QIDS-SR item 12)

- Side- effec ts and severity of manic, psy-

chotic and dissociative symptoms.

Jafarinia et al.,

2016

Ketamine vs Diclofenac Age 20–55 years, patients with TRD,

chronic mild-moderate headache

HDRS at week 3 and 6, HADS Comparison of changes in HDRS scores

from baseline to each time point,

response to treatment (defined as ≥50%

reductionintheHDRSscore),

remission (defined as HRDS score ≤ 7),

and severity of pain intensity between

the treatment groups and evaluation of

the antidepressant effects of each drug

separately.

Jarventausta K.

et al. 2013

S-Ketamine & propofol vs Normal

saline & propofol

Age 18–80 years, participants with

TRD with failure of two

antidepressants in the past.

MADRS Not mentioned

Jiang M. , et al.,

2016

Ketamine vs Control Age 18–60 years, patients undergoing

orthopedic surgery

PHQ-9 Not mentioned

Tayyebi et al.,

2018

Ketamine bolus vs infusion Age 20–60 years, patients with MDD HDRS, BDI Not mentioned

Lai R. et al., 2014 Ketamine at different doses vs

saline

Participants with TRD, Age

29–66 years, MADRS score of ≥

□20

MADRS SAFTEE scale

Psychiatric Quarterly

Table 1 (continued)

Study Design Inclusion Criteria Primary Outcome Secondary Outcome

Lapidus et al.,

2014

Ketamine vs Placebo Age 21–65 years, MDD, baseline

score of ≥30 on the Inventory of

Depressive

Symptomatology—Clinician Rated

(IDS-C)

MADRS at 24 h after treatment Systematic Assessment for Treatment

Emergent Effects (SAFTEE)

Lenze et al., 2016 Saline infusion followed by

Ketamine

40 min infusion vs 96 h infusion

Age 18–65 years, MDD, MADRS

score of ≥

MADRS Not mentioned

Lo et al., 2016 Ketamine vs Midazolam Participants, ages ≥18 years , major

depressive disorder and a depressive

episode of duration ≥4weeks.

Change in MADRS scores BPRS, YMRS, CADSS

Murrough et al.,

2016

Ketamine vs Midazolam Age 21–80, with MDD, and

inadequate response to at least three

therapeutic trials of an

antidepressant

Change in MADRS scores 24 h after

infusion

MADRS response rate, change in score on

the Quick Inventory of Depressive

Symptomatology—Self-Report, scores

on the Clinical Global Impression (CGI)

severity and improvement measures,

and durability of benefit for up to

7 days following infusion.

Fava et al., 2018 Ketamine vs Midazolam Age 18–70 years old patient with TRD

MDD, current major depressive ep-

isode

HAM-D-6

2- groups comparison = Ketamine vs

Midazolam

5-groups comparison between all four

doses of Ketamine and placebo

MADRS, CGI-S, CGI-I, SDQ, and PAS

Fernie et al., 2017 Ketamine vs Propofol Age 18–70 years with MDD receiving

ECT on an informal basis, consid-

ered fit by an anesthetist, had no

comorbid psychiatric diagnoses

HRSD, MADRS Cognitive function, assessed before ECT

using the Cambridge Automated

Neuropsychological Test Battery

Spatial

Recognition Memory task (CANTAB

SRM)

Daly et al., 2017 Esketamine vs Placebo Age 20–64 years, TRD MDD and IDS

score ≥ 34

Change in MADRS Clinical Global Impression of Severity

scale

Severity of anxiety on the Generalized

Anxiety Disorder 7-item scale

Psychiatric Quarterly

Table 1 (continued)

Study Design Inclusion Criteria Primary Outcome Secondary Outcome

Grunebaum et al.,

2018

Ketamine vs Midazolam 18 to 65 years, adults with current

MDD, HDRS-17 score ≥ 16 and

score ≥ 4ontheScaleforSuicidal

Ideation (SSI)

SSI Differential change between groups in SSI

and depressive sympt oms (HDRS17

and 24, BDI, POMS)

Kudoh et al., 2002 Propofol, Fentanyl, Ketamine vs

Propofol and Fentanyl

Participants, ages 35 to 63 years for

intervention group and 30 to

64 years for control group), all

patients with MDD, undergoing

orthopedic surgery.

The control group did not have any

psychiatric illnesses.

Change in HDRS scores Postoperative confusion assessed using

confusion assessment method (CAM),

pain was estimated using a 100 mm

visual analog scale

Salehi et al., 2015 Ketamine vs Sodium thiopental Age 20 and 60-year-old, TRD HMDRS Blood pressure

Singh et al., 2016 Ketamine vs Placebo 18–64 years old adults, recurrent

MDD- TR without psychotic

features, and a score of 34 on the

30-item Inventory of Depressive

Symptomatology–Clinician rated .

Change in MADRS scores Early onset of clinical response, total

number of responders at day15, total

Change in MADRS score from baseline

through day 29, Clinical Global

Impressions severity score (CGI-S),

CGI improvement score (CGI-I),

Patient Global Impression severity

score (PGI-S), Patient Global

Impression of Change score (PGI-C)

Singh et al., 2016 Esketamine vs Placebo 18–64 years old adults, recurrent

MDD- TR without psychotic fea-

tures.

Change in MADRS scores 24 h. change in MADRS total score from day 1

to day 3 and day 4 and from day 4 to

day 7, change in MADRS total score

from day 1 to day 35, change in the

Quick Inventory of Depressive

Symptomatology–Self Report, Clinical

Global Impression–Severity, Clinical

Global Impression–Improvement, Pa-

tientGlobalImpression of Severity, and

Patient Global Impression of Change.

Psychiatric Quarterly

Table 1 (continued)

Study Design Inclusion Criteria Primary Outcome Secondary Outcome

Sos et al., 2013 Ketamine vs Placebo Participants with MDD, ages18 and

65 years old, MADRS score of 20

MADRS score change at day 1, 4 and

7 betwe en ketamine and placebo

Response rates

Plasma levels of ketamine and its

metabolite nor-ketamine during keta-

mine and placebo infusion at baseline,

10 mins, 30 mins of the infusion)

Su et al., 2017 Ketamine vs Placebo All patients with Treatment-resistance

MDD, score of more than 18 on

HAMD

HAMD-17 scores Response rate, dose group Responder vs

BDNF genotype, Predictor of response

and sustained effe ct

Wang et al., 2012 Ketamine vs Propofol vs Ketamine

&Propofol

Patient with MDD and score ≥ 20 on

HDRS.

Change in HDRS scale None mentioned

Xu et al., 2017 Ketamine vs Control Women age between 30 and 35 years,

who underwent modified radical

mastectomy of unilateral breast.

HAMD score of ≥17.

Change in HAMD scores Not mentioned

Xu et al., 2017 Ketamine vs Saline American Society of Anesthesiologists

(ASA) grade 1–2 and elective cae-

sarean deliverywithspinal

anaethesia.

For prevention of depression

EPDS Numeric rating scale score of pain

Yoosefi et al.,

2014

Ketamine vs Thiopental 20–50 years old, MDD and

HAM-D ≥ 18.

Mean change in HAM-D scores The effects of ketamine and thiopental on

the cognitive consequences, seizure

parameters, and hemodynamic factors

of ECT

Zarate et al., 2006 Ketamine vs Placebo Participants with treatment- resistant

MDD, ages 18–65 years old,

HDRS score of ≥18.

Mean change in HDRS-21 scores Beck Depression Inventory (BDI), Brief

Psychiatric Rating Scale (BPRS) posi -

tive symptoms subscale, Young Mania

Rating Scale (YMRS).

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Alizadeh et al.,

2015

IV Ketamine 0.3 mg/kg per

ECT session

5 ml of normal saline Primary:

Mean HDRS scores

Baseline scores

The HDRS scores were similar among both

groups with similar recovery time and

speed.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Ketamine = 35.4 ± 6.7

Placebo = 36.44 ± 7.17

Study endpoint

Ketamine = 14.18 ± 11.83

Placebo = 14.33 ± 9.46

Secondary: NA

Arabzadeh et al.,

2018

Oral Ketamine 50 mg/day

All patients received

25-150 mg/day sertraline

Oral 50 mg/day placebo

All patients received

25-150 mg/day sertraline

Primary:

Change in HDRS scores = −3.41 (−5.07 to

−1.75)

Secondary outcome measures:

1) At 4 weeks: −2.61 (−4.11 to −1.11) and at

6 weeks:

−1.91 (−3.34 to −0.48)

2) Ketamine (85.4%) vs Placebo (42.5%).

3) Ketamine (85.4%) vs Placebo (57.5%)

4) Ketamine (22.0%) vs Placebo (15.0%)

- Significant difference between Ketamine and

placebo group was observed at week 2, 4,

and 6.

- Early improvement and response rate was

greater in Ketamine (85.4%, 85.4%)

compared to the placebo group (42.5%,

57.5%), respectively.

- The remission rates were similar among both

groups.

Burger et al., 2016 IV Ketamine 0.2 mg/kg

over 2 min

IV Normal saline infused over

2min

Primary:

2/3 participants reported improvement in

suicidal ideations within 40 min in

suicidality while no improvement was

reported in placebo group.

Secondary: NA

Two of three who received ketamine reported

improvement in suicidality and hopelessness

compared to none among the control group.

Canuso et al.,

2018

Intranasal 84 mg

Esketamine.

Intranasal 84 mg Place b o. Primary:

1) Change in MADRS:

Esketamine group = −13.4 SD = 9.03)

Placebo group = −9.1 (SD = 8.38)

2) Esketamine VS Placebo: 21.2% and

9.7%, respectively

Secondary:

1)MADRSat24h:leastsquaremean

difference = 27.2, SE = 2.85, at day 25:

least-square mean difference = 24.5, SE =

3.14.

- The MADRS scores improved four hours

after the first dose in both groups, with a

greater improvement in Esketamine group.

- A greater improvement was reported among

Esketamine group compared to placebo

group at all stud timepoint during blinded

phase.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

2) At 24 h

after the first dose: 40.0% and 6.5%, respectively,

and at day 25: 69% and 61% respectively

Carspecken et al.,

2018

IV racemic Ketamine

1–2mg/kg

IV Methohexital 1 to 2 mg/kg Primary:

HAM-D: Ketamine (F1,45 = 7.8, MSE =333.6,

P = 0.008, ηp2 = 0.16) vs Methohexital

(F1,45 = 0.43, mean square error

[MSE] = 18.4, P =0.51,ηp2 = 0.01)

PHQ-9: Ketamine (F1,47 = 6.45, MSE =140.4,

P = 0.01, ηp2 = 0.13) vs Methohexital

(F1,47 = 0.96, MSE = 21, P =0.331,

ηp2 = 0.02)

PHQ-9

Baseline scores:

Ketamine = 21.1 (±3.9)

Methohexital = 21.5 (±3.6)

Study Endpoint:

Ketamine = 7.2 (±4.4)

Methohexital = 8.7 (±5.3)

HAM-D

Baseline scores:

Ketamine = 27.6 (±8.7)

Methohexital = 28.8 (±5.2)

Study Endpoint:

Ketamine = 12.3 (±7.6)

Methohexital = 15 (±6.9)

Secondary:

MOCA

Baseline scores:

Ketamine = 27.4 (±2.0)

Methohexital = 26.7 (±3.9)

Study Endpoint:

Ketamine = 25.6 (±3.8)

- Patients in both groups reported improvement

after the ECT course.

- Plasma BDNF increased after ECT only in

the ketamine group

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Methohexital = 24.4(±4.1)

Chen et al., 2017 IV Ketamine, 0.3 mg/kg.

All patient received ECT

treatment.

IV Normal Saline 0.3 mg/kg.

All patient received ECT

treatment.

Primary:

The occurrence global cognitive impairment in

the control group was higher than it was in

the study group.

ThedeclineintheWechslerMemory

Scale-Chinese- Revision scale was greater in

the control group than in the study group.

Secondary:

The overall remission rates in the control group

and the study group were 68% and 74%

respectively with no significant difference

among both groups.

- The overall remission rates were 74% and

68% for the Ketamine and control group

respectively.

- There was no statistically significant

difference among both groups.

- The median ECT times were 8 for ketamine

and 9 for the control group.

- The total number of ECT procedures were

511 for Ketamine and 584 for control group.

Fan et al., 2017 IV 0.5 mg/kg racemic

ketamine hydrochloride

over 40 min

IV 0.05 mg/kg

midazolam over 40 min

Primary:

BSI Scores

Baseline scores:

Ketamine = 17.06 (SD = 1.819)

Midazolam = 16.6 (SD = 2.137)

At day 3:

Ketamine: 1.69 (SD = 1.93)

Midazolam: 3.42 (SD = 1.75)

MADRS-SI

Baseline scores:

Ketamine=3.65(SD=1.173)

Midazolam = 3.65 (SD = 1.268)

At day 3:

Ketamine=1.77(SD=1.84)

Midazolam = 3.52 (SD = 1.89)

Secondary:

MADRS Scores

Baseline scores:

Ketamine = 34.89 (SD = 8.04)

Midazolam = 34.19 (SD = 10.83)

- The improvement on MADRS score was

noticed on day 1 and continued on day 3,

but it was not observable day 7 following

treatment.

- There was also improvement in suicidal

ideations on BSI and MADRS-SI.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

At day 3:

Ketamine: 25.09 (SD = 7.07)

Midazolam: 32.03 (SD = 7.21)

At 7 days: difference was insignificant.

Gamble et al.,

2018

IV Ketamine, 0.75 mg/kg

and remifentanil 1

mcg/kg

All patients received 8 ECT

sessions

IV Propofol 1 mg/kg and

remifentan il 1 mcg/k g

All patients received 8 ECT

sessions

Primary:

All patients in the ketamine arm achieved a

50% MADRS reduction compared with 10

(83%) in the Propofol arm.

Median interquartile range [IQR] number of

ECT treatments to achieve a 50% MADRS

reduction is 2 [1–4] for Ketamine and 4

[2–7] for propofol group.

Secondary:

- All patients in the ketamine group achieved

remission compared with 7 in the propofol

group 3 ECT treatments com par ed with 7

treatments for propofol.

- Patients in the ketamine group were more than

twice as likely to ach ie ve respo ns e on

MADRS [HR]: 3.20, 95% co nfid e nce

interval [(CI)]: 2.00 to 5.13 and also were

also twice as likely to achieve remission

(HR: 3.67, 95% CI: 2.13 to 6.32) compared

with the propofol arm.

- A comparable change in ALS scores were

reported among both groups.

-Mean CADSS scores were comparab le among

both groups.

- Time from anesthesia to discharge was similar

between groups, 63.5 (18.2) vs 63.3 (15.8)

minutes in the ketamine arm and propofol

arm, respectively.

- About 100% patients in Ketamine group

achieved 50% reduction in MADRS

compared to placebo.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Ghasemi et al.,

2013

IV Ketamine, 0.5 mg/kg

over 45 min, 3 infusions

for45minover3days

ECT on 3 test days (every 48 h) Primary:

BDI Sco res

Baseline scores:

Ketamine = 34.66 (SD = 10.7)

ECT = 42.44 (SD = 9.53)

After one-week post treatment

Ketamine:10.88 (SD = 7.49)

ECT: 15.66 (SD = 7.51)

HDRS Scores

Baseline scores:Ketamine = 30.22 (SD = 5.78)

ECT = 35.88 (SD = 6.47)

After one-week post treatment

Ketamine:9.55 (SD = 4.98)

ECT: 14 (SD = 4.9)

Secondary: NA

- There was a significant improvement in

patient receiving Ketamine compared to

placebo group within 24 h of first infusion.

- This improvement was observed throughout

the study after second treatment and 72 h

post-treatment.

- The effect size were moderate to large

throughout the study.

Haile et al., 2013 IV Ketamine, 0.5 mg/kg,

Single dose for 40 min

for 7 days

Midazolam 0.045 mg/kg Primary:

Seven patients receiving ketamine met

response criteria at day 7, whereas two

patients receiving midazolam met response

criteria.

Secondary: NA

- Participants taking Ketamine reported an

increased in plasma BDNF levels compared

to non-responsders.

- There was highly significant negative

correlation between MADRS and BDNF

levels with ketamine (240 min post

infusion).

-BDNFcanbeusedasperipheralbiomarker

for ketamine antidepressant response.

Hu et al., 2015 IV Ketamine, 0.5 mg/kg

Oral

Escitalopram = 10 mg/-

day

IV Normal saline (placebo)

Oral Escitalopram = 10 mg/day

Primary:

Change in MADRS scores

Baseline scores:

Ketamine = 32.3 (SD = 6.5)

Placebo = 36.5 (SD = 7.8)

Afterfourweeks:

Ketamine:14.0 (SD = 10.2)

Placebo: 18.1 (SD = 8.2)

Secondary:

- Response rate was 92.3% and 57.1% for

Ketamine + Escitalopram and placebo +

Ketamine group, respectively.

- For TRD, the response rate was 88.9% and

33.3% for Ketamine + Escitalopram and

placebo + Ketamine group, respectively.

- The remission rate was 76.9% and 14.3% for

Ketamine + Escitalopram and placebo +

Ketamine group, respectively.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Response:

At 4 weeks:

Ketamine vs Placebo: 92.3% vs 57.1%

Remission:

At 4 weeks:

Ketamine vs Placebo: 76.9% vs 14.3%

QIDS-SR

Baseline scores:

Ketamine = 16.5 (SD = 5.3)

Placebo = 17.5 (SD = 4.2)

Afterfourweeks:

Ketamine:7.8 (SD = 5.8)

Placebo: 10.0 (SD = 4.6)

QIDS- Suicide

Baseline scores:

Ketamine = 1.9 (SD = 0.7)

Placebo = 1.4 (SD = 0.6)

Afterfourweeks:

Ketamine:0.4 (SD = 0.9)

Placebo: 0.2 (SD = 0.4)

- Patients receiving Ketamine observed quicker

improvement than placebo.

Jafarinia et al.,

2016

Oral Ketamine 50 mg three

times daily

Diclofenac 50 mg three times

daily

Primary:

HDRS M ean difference: ketamine −diclofenac

at week 3: 1.85 (−0.48 to 4.18) and at week

6: (95% CI): 2.85 (0 .5 4 to 5.16)

HADS Mean difference for

ketamine-dicolfenac at week 3: ketamine−-

diclofenac (95% CI): 1.05 (0.45 to 1.64),

and week 6:(95% CI): 0.75 (0.18 to 1.32)

Secondary:

Mean VAS score between keta min e and

diclofenac at week 3: 2.05 (−8.27 to 12.37)

and week 6:(95% CI): −2.90 (−18.07 to

12.27)

- A significant dec rease in HDRS scores was

observerd with ketamine compared to

placebo.

- However, both groups were comparable at

week 3.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Jarventausta K.

et al. 2013

IV Ketamine, 0.4 mg/kg IV Normal saline & Propofol. Primary:

Change in MADRS score:

S-ketamine = −26.9 ± 9.5

Normal saline & propofol = −27.1 ± 7.9

Secondary: NA

- There was a comparable reduction in

MADRS scores among both groups.

- The was no difference in speed of response

and number of ECT sessions.

Jiang M. , et al.,

2016

0.5 mg/kg (0.05 ml/kg)

ketamine was

given at induction of

anesthesia, followed by

0.25 mg/kg/h

(0.025 ml/kg/h)

continuous infusion for

30 min.

0.05 ml/kg Ketamine was used at

induction of anesthesia,

followedby0.025ml/kg/h

continuous infusion of saline

for 30 min.

Primary:

Difference in PHQ-9 scores for Ketamine

group preoperatively to pos tope ra tiv ely

(days 1 and 5): (t-valu e = −2.144,

F=−14.67, P <0.01)

PHQ scores

Preoperation

Control = 3.63 ± 0.14

Ketamine = 4.02 ± 0.13

Postoperative day 5

Control = 2.92 ± 0.63

Ketamine = 2.28 ± 0.61

Secondary: NA

- There was a significant decrease in PHQ-9 of

Ketamine group compared to placebo at

postoperative day 1 and 5.

- BDNF levels were higher in Ketamine group

after surgery.

Tayyebi et al.,

2018

IV Ketamine Bolus and

infusions,

0.5–0.75 mg/kg

NA Primary:

AccordingtoHamiltonandBeckscore,the

treatment response in investigated patients

was 64% and 60%, respectively.

About 48% participants on HDRS and 44% on

BDI responded to treatment on injection

0.5 mg/kg compared to 80% on HDRS and

76% on BDI on injection 0.75 mg/kg/

Secondary: NA

- Abo ut 64% and 60% patients reported

improvement on HDRS and BDI,

respectively.

- For dose of 0.5 mg/kg of Ketamine, 48% and

44% reported response on HDRS and BDI,

respectively.

- For dose of 0.5 mg/kg of Ketamine, 80% and

76% reported response on HDRS and BDI,

respectively.

- The positive response was highest during first

two days and at week1.

Lai R. et al., 2014 IV Ketamine,

0.1–0.4 mg/kg

IV Normal Saline Primary:

Baseline MADRS score, 29, 27,29, 28

Three of four subjects achieved antidepressant

response (50% decrease in MADRS scores)

- For two patients, response was noticed at

0.1 mg/kg.

- For other two, response was observed at the

highest doses.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Secondary: NA - All patients relapsed within a week.

Lapidus et al.,

2014

Intranasal Ketamine,

50 mg/day

Intranasal Normal saline Primary:

Estimated mean difference in MARDS score

between ketamine and placebo was 7.6

(95% CI: 3.9–11.3)

Secondary: NA

- At 24 h, there was significant improvement

among Ketamine (44%) compared to

placebo (6%).

- Ketamine was associated at 40 min, 4 and

48 h.

- No difference was observed at 72 h or 7 days.

Lenze et al., 2016 IV Ketamine, 0.5 mg/kg NA Primary:

Baseline score for MADRS

Saline&40-min infusion group = 34.0 (3.8)

96- h infusion group = 31.9 (5.9)

50% reduction in MADRS:

4/10 in the 96-h group and 2/10 in the 40-min

group were respond ers at week 2; of these,

2/10 in the 96-h group and 1/10 in the

40-min group maintained response out to

week 8.

Secondary: NA

- Both groups reported a significant reduction

in depressive symptoms compared to

baseline.

- Higher Ketamine concentration was

associated with a better antidepressant

response.

Lo et al., 2016 Ketamine = 0.1 mg/kg,

increasing by 0.1 mg/kg

up to 0.5 mg/kg.

Ketamine was given in three

routes including IV, IM,

SC.

Midazolam 0.01 mg/kg Primary:

12/15 participants met the criteria for both

response and remission at least at one time

point during the trial (across all dose levels

and time points).

The overall acute response/remission rates

were75% for IV, 60% for IM, and 100% for

SC groups.

Secondary:

There was no evidence of treatment emergent

mania at any of study time point, across

routes of administration and doses.

There was no clinically significant change in

BPRS or CADSS was observed in the

- 12/15 participants achieved response and

remission at least at one time point during

the trial.

- The response and remission rates were 75%

(IV), 60% (IM) and 100 % (SC).

- Dose-dependent response but also led to

increased side effects.

- The mean time to relapse was 23.2 days for

all routine, 9 days for IV group, 11.7 days

for IM group, and 34.5 days for SC group.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

midazolam compared to different routes of

ketamin e.

Murrough et al.,

2016

Single IV infusion of

Ketamine Hydrochloride

0.5 mg/kg

Single IV infusion of Midazolam

0.045 mg/kg

Primary:

Change in MADRS scores

Baseline scores:

Ketamine = 32.6 (SD = 6.1)

Placebo = 31.1 (SD = 5.6)

After 24 h:

Ketamine = 14.77, 95% CI (11.73–17 .8 0)

Placebo = 22.72, 95% CI (18.85–26.59)

Secondary:

- MADRS Response rate = Ketamine 64% VS

Placebo 28%

- CGI-I=Ketam ine 62% VS Placebo 24%

- CGI-S=Ketamine 53% VS Placebo 8%

QIDS scale

Baseline scores:

Ketamine = 16.6 (SD = 4.1)

Placebo = 16.3 (SD = 4.5)

After 24 h:

Ketamine = 8.38, 95% CI (6.71–10.05)

Placebo = 11.78 , 95% CI (9.63–13.92)

- The response rates were 64% for Ketamine

and 28% for placebo, respectively at 24 h

with number need to treat of 2.4.

- There was a small worsening of symptoms

over time but depression scores were lower

for Ketamine group.

Fava et al., 2018 IV Ketamine 0.1 mg/kg,

0.2 mg/kg, 0.5 mg/k and

1.0 mg/kg.

IV Midazolam 0.045 mg. Primary:

Pairwise comparisons of all ketami ne group

to midazolam on HAM-D-6 at day 3

−1.87, 95% CI (−4.14, 0.41)

Pairwise comparisonsofeachketamine

group to midazolam on HAM-D- 6 at day

0.1 mg/kg = −2. 0 4, 95% CI (−5. 0 4, 0.95)

0.2 mg/kg = −0. 3 6, 95% CI (−3. 1 8, 2.46)

0.5 mg/kg = −3. 2 1, 95% CI (−5. 9 7, −0.44)

1.0 mg/kg = −1. 8 4, 95% CI (−4. 6 5, −0.96)

- IV Ketamine was superior to active placebo

within 72 h of treatment.

- The dose of 0.5 mg and 1.0 mg/kg was

superior to placebo and lower doses of

ketamine.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Secondary:

Statistical significance of the group*time

interaction effect was significant for only for

the SDQ (p = 0.0105) and the PAS

(p = 0.0341) in the 5-group comparison, and

the PAS (p = 0.0332) and the CGI-S

(p = 0.0204) in the 2-group comparison.

Fernie et al., 2017 IV Ketamine up to 2 mg/kg

All partic ipa nts received

ECT.

IV Propofol up to 2.5 mg/kg

All participants received ECT.

Primary:

Change in HDRS scores

Baseline severity

Ketamine = 27.19 (6.47)

Propofol = 24.79 (8.50)

After one month post-ECT

Ketamine = 14.08 (8.08)

Propofol = 12.08 (9.86)

Change in MADRS scores

Baseline severity

Ketamine = 36.38 (8.29)

Propofol = 35.68 (8.39)

After one month post-ECT

Ketamine = 17.85 (13.15)

Propofol = 17.15 (13.75)

Secondary:

CANTAB SRM

Baseline severity

Ketamine = 0.71 (0.11)

Propofol = 0.72 (0.15)

After one month post-ECT

Ketamine = 0.70 (0.11)

Propofol = 0.65 (0.12)

ketamine as an anaesthetic agent for ECT was

not associated with acceleration of the

antidepressant effect of ECT

Daly et al., 2017 Intranasal Esketamine

28 mg, 56 mg, 84 mg.

Intranasal placebo Primary:

Mean difference from placebo

Esketamine 28 mg: −4.2 (2.09)

- There was dose-dependent statistically sig-

nificant treatment among all treatment

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Esketamine 56 mg: −6.3 (2.07

Esketamine 84 mg: −9.0 (2.13)

Secondary:

Baseline and last day

groups compared to placeb o after a week of

treatment.

- Duration of effectiveness with 28 mg dose

was shorter.

Grunebaum et al.,

2018

IV Ketamine 0.5 mg/kg IV midazolam 0.02 mg/kg in

100 ml normal saline

Primary:

Average SSI score at day 1:

Difference between Ketamine to

Midazolam = 4.96 (95% CI 2.33 to 7.59)

Secondary:

- The proportion of responders on SSI was 55%

after ketamine compa re d to Midazo lam at

day 1.

- POMS Scale improvement after ketamine

compared with

midazolam = (Estimate = 21.19 (95%

CI = 2.95 to 39.43).

- Depression = Estimate = 7.65 (95% CI = 1.36

to 13.94)

- Change in HDRS-17 = Estimate = 2.83 points

(95% CI = −0.12 to 5.77).

- Change in HDRS-24 = 3.54 points (95%

CI = −0.29 to 7.36)

Self-rated BDI = 4.66 points (95% CI = −0.0 4

to 9.36).

A single Ketamine infusion resulted in a

greater reduction in suicidal ideations at day

1 compared to active placebo. The Ketamine

groups showed a greater improvement for

depression compared to active placebo.

Kudoh et al., 2002 Group A: Single IV infusion

of 1.0 mg/kg of

Ketamine, 1.5 mg/kg of

Propofol, and 2 μg/kg of

Fentanyl

Group B: Single IV infusion of

1.5 mg/kg of Propofol and 2

μg/kg of Fentanyl

Primary:

Change in HDRS scores

Baseline scores:

Group A = 12.7 ± 5.4

Group B = 12.3 ± 6.0

Group C = 4.2 ± 1.7

After surgery:

Group A = 9.9 ± 4.1

Group B = 14.4 ± 3.8

Small-dose ketamine not only improved the

depressive symptoms postoperatively but

alsoreducedpainindepressedpatientswho

underwent orthopedic Surgery. Depressed

mood, suicidal tendencies, somatic anxiety,

and hypochondriasis significantly decreased

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Group C = 4.8 ± 1.6

Secondary:

Postoperative pain scores in Group A at 8 and

16 h after the anesthetic effect were

significantly lower than those in Group B.

There were no significant differences in the

other postoperative pain scores between two

groups for 4 days after su rger y . P

Postoperative pain scores for Group C at 8, 16,

24, 48, and 72 h were 20.2 □ 8.4, 18.4 □ 7.5,

11.9 □ 6.1, 8.7 □ 5.5, and 5.2 □ 3.2 ,

respectively after the end of anesthesia.

Salehi et al., 2015 IV Ketamine 0.8 mg/kg

Participants received a total

of eight ECT sessions.

IV Sodium thiopental

1mg/kg-1.5mg/kg

Participants received a total of

eight ECT sessions.

Primary:

Change in HMDRS scores

Baseline scores:

Ketamine = 29.82 ± 7.3

Sodium thiopental = 28.86 ± 7.6

After session#8:

Ketamine = 8.32 ± 5.17

Sodium thiopental = 10.53 ± 7.87

Secondary:

Systolic and diastolic blood pressure have

statistically significant difference between

ketamine and sodium thiopental in all

sessions .

The depression score s improved after each

ECT session but improvement was faster in

Ketamine group.

Singh et al., 2016 Intravenous

Ketamine (0.5 mg/kg) two

or three times weekly

Intravenous

placebo (0.9% Sodium chloride

for injection) two or three

times weekly

Primary:

Change in MADRS score

Ketamine twice daily: 218.4 (SD = 12.0)

Placebo = 25.7 (SD = 10.2)

Ketamine three times daily = 217.7 (SD = 7.3)

Placebo = 23.1 (SD = 5.7)

Secondary:

Ketamine was effective at both frequencies for

depression compared to placebo.

The mean difference in MADRS scores was

comparable among both groups.

Onset of antidepressant was noticed within first

week and was maintained through day 15

for both Ketamine group compared to

placebo.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

The total change in MADRS score from

baseline to day 29 for both ketamine

groups

Ketamine twice a daily = 221.2 (SD = 12.9)

Placebo = 24.0 (SD = 9.1)

Ketamine three times daily = 221.1 (SD = 11.2)

Placebo = 23.6 (SD = 6.6)

MADRS response at day 15

Ketamine twice a daily vs placebo = 68.8% vs

15.4%

Ketamine three times a daily vs placebo = 6.3%

vs 53.8%

MADRS remission at day 15

Ketamine twice a daily vs placebo = 7.7% vs

37.5%

Ketamine three times a daily vs placebo = 0%

vs 23.1%

MADRS onset of response in week 1

Ketamine twice a daily vs placebo = 6.3% vs

38.9%

Ketamine three times a daily vs placebo = 0%

vs 4%

During the 2-week open-label ketamine phase,

the mean CGI-S and PGI-S scores were

similar in both groups

The treatment response was similar among

both groups during open-label phase.

Singh et al., 2016 Single IV Esketamine

0.20 mg/kg, or single IV

Esketamine 0.40 mg/kg

over 40 mins

Single IV infusion of placebo

(.9% saline solution) Over

40 mins

Primary: Change in MADRS score

compared to placebo

Placebo = 23.8 (SD = 2.97)

Esketamine .20 mg/kg = 216.8 (SD = 3.00)

Esketamine .40 mg/kg = 216.9 (SD = 2.61)

Secondary:

The total change in MADRS score from

baseline to day 3

- The depression scores improved for both

groups taking Esketamine groups compared

to plac ebo.

- The proportion of responders were 67% and

64% for both Esketamine groups. There

were no responders among placebo group.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Placebo = −2. 3 (SD = 3.38)

Esketamine .20 mg/kg = −16.3 (SD = 3.45)

Esketamine .40 mg/kg = −13.4 (SD = 3.03)

Responders to first dose

Esketamine 0.2 mg/kg = 67%

Esketamine 0.4 mg/kg = 64%

Placebo = 0%

Change in CGI-S score

Placebo = −0. 2 (SD = 0.63)

Esketamine .20 mg/kg = −1.3 (SD = 1.5)

Esketamine .40 mg/kg = −1.4 (SD = 1.36)

Change in PGI-S score Placebo = −0.3

(SD = 0.48)

Esketamine .20 mg/kg = −0.8 (SD = 0.97)

Esketamine .40 mg/kg = −.6 (SD = 0.82)

Sos et al., 2013 Single IV loading dose of

0.27 mg/kg followed by

maintenance dose of

0.27 mg/kg

Single IV infusion of placebo

(.9% saline solution)

Primary:

Change in MADRS total score

Day 1 = 5.7 (95%CI 3.4–7.9)

Day 4 = 4.7 (95%CI 2.5–7.0)

Day 7 = 4.0 (95% CI 1.8–6.2

Secondary:

Response rates at day 7

Ketamine = 40.7%

Placebo = 11.1%

Ketamine serum levelsAfter

10 min = 306 ± 136 ng/ml

After 30 min =237 ± 95 ng/ml

Ketamine metabolite levels

After 10 min = 11 ± 7 ng/ml

After 30 min = 50 ± 21 ng/m..

There were no differences found between

responders and non-responders in ketamine

and/or nor-ketamine serum levels.

There was a reduction in the core symptoms of

depression in the following week with

maximum on day seven.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Su et al., 2017 IV Ketamine = 0.2 mg/kg,

0.5 mg/kg.

Single IV infusion of placebo

(saline solution)

Primary: HAM-D Scores

Baseline severity (Estimated Least Square

Means):

Placebo = 1.32

Ketamine 0.2 mg/kg = 1.32

Ketamine 0.5 mg/kg = 1.32

At 28 days (Estimated Least Square Means):

Placebo = 1.11

Ketamine 0.2 mg/kg = 0.91

Ketamine 0.5 mg/kg = 0.96

Secondary:

Response rates

Ketamine 0.5 mg/kg = 45.8%

Ketamine 0.2 mg/kg = 39.1%

Placebo = 12.5%

Response Rate by BDNF Val66Met

Genotype

Val/Val = 17%

Val/Met = 56.3%

Met/Met = 26.8%

There was no differences betwe en carriers of

the Met allele and Val/Val patients (re-

sponder rate: 33.9% vs 25.0%).

BDNF genotype is not a significant predictor of

the outcome.

The dose of 0.5 mg/kg was more effective

compared to 0.2 mg/kg and placebo.

There was no significant difference between

carriers of the Met allele and Val/Val pa-

tients in efficacy for Ketamine

Wang et al., 2012 Single IV dose of

0.8 mg/kg, Ketamine or

Single IV dose of

0.8 mg/kg Ketamine plus

1.5 mg/kg Propofol

All partic ipa nts received

ECT.

Single IV dose of 1.5 mg/kg

Propofol

All participants received ECT.

Primary: Change in HDRS scores

Baseline severity

Ketamine & propofol = 28.00 ± 4.88

Ketamine = 27.00 ± 3.93

Propofol = 28.16 ± 2.48

After 7 days

Ketamine & propofol = 6.94 ± 1.57

Ketamine = 6.75 ± 0.96

The HDRS scores improved quickly in

ketamine group and Ketamine and Propofol

group compared to Propofol only group.

The improvement in depression scores were

significantly greater in ketamine group and

Ketamine and Propofol group compared to

Propofol only group.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

Propofol = 11.08 ± 2.78

Secondary:

Xu et al., 2017 IV Ketamine 0.5 mg/kg. Isofibrillar saline Primary:

Change in HAMD scores

Baseline severity

Ketamine = 18.82 ± 2.82

Control group = 18.55 ± 3.21

After 7 days

Ketamine = 17.36 ± 6.25

Control group = 13.45 ± 5.21

Secondary:

The HAMDS scores improved at day 1, 3 and

7 compared to placebo.

However, this change was not statistically

significant.

Xu et al., 2017 Single IV dose of

0.25 mg/kg Ketamine

Single IV infusion of placebo

(.9% saline solution)

Primary:

EDRS score s 3 days postpa rtum

Ketamine = 7.2 ± 3.9

Saline = 7.2 ± 4.2

EDRS scores 6-weeks postp ar tu m

Ketamine = 5.6 ± 3.9

Saline = 5.7 ± 4.3

Occurrence of postpartum depression

Ketamine = 16%

Saline = 17.8%

Secondary:

NRS scores 3 days postpartumKetamine = 4

(0–7)

Saline = 4 (0–8)

NRS scores 6-weeks postpartum

Ketamine = 1 (0–8)

Saline = 2 (0–9)

No significant differences were found in the

prevalence of postpartum depression

Yoosefi et al.,

2014

IV infusion of ketamine

1 mg/kg or 2 mg/kg,

IV infusion of thiopental

2 mg/kg or 3 mg/kg,

Primary:

Change in HAMD scores

Baseline severity

- There was significant in depression scores

among Ketamine group before second ECT

session compared to Thiopental.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

ECT sessions were carried

out 3 times a week for a

total of 6 sessions over

3weeks

ECT sessions were carried out 3

times a week for a total of 6

sessions over 3 weeks

Ketamine = 23.60

Thiopental = 22.8 6

After 4 days

Ketamine = 17.07

Thiopental = 17.2 9

Secondary:

Change in MMSE scores

Baseline severity

Ketamine = 25.60

Thiopental = 24.7 9

After 4 days

Ketamine = 27.87

Thiopental = 25.2 9

Seizure parameters

Ketamine seizure duration = 27.47 to 31.87 s

Ketamine electrical dose = 28.67 to 36

Thiopental seizure duratio n = 19. 27 to 25.5 7 s

Thiopental electrical dose = 36.43 to 62.86

In both groups, baseline values of heart and

Mean Arterial Pressure were not shown to

be significantly different.

- At the end of study, both groups observed an

improvement in depre ssio n scores.

Zarate et al., 2006 Single IV dose of 0.5 mg/kg

Ketamine in two phases

Single IV infusion of placebo

(saline solution)

Primary:

Change in HDRS scores

Ketamine = −56.2 ± 20.4

Placebo = −9. 8 ± 20.1

Secondary:

BPRS positive symptoms subscale scores for

participants receiving Ketamine

compared to placebo

Drug, F1,200 = 4.23; P =.04;time,

F8,200 = 9.31; P□.001; drug □ time,

F8,200 = 6.89; P□.001)

Ketamine was effective for depression

compared to placebo. This benefit was

maintained for a week after the Ketamine

dose.

Psychiatric Quarterly

Table 1 (continued)

Study Intervention group Comparison group Mean change in primary outcome measures Summary of results.

YMRS scores for participants receiving

ketamine compare d to placebo

Days 1 to 2 (drug, F1,201 = 3.08; P =.08;time,

F8,201 = 3.54; P□.001; drug □ time,

F8,201 = 4.68; P□.001

Response rates

Ketamine = 71%

Placebo = 0%

Remission rates

Ketamine = 35%

Placebo = 0%

BHS, Beck Hopelessness Scale; BSI, Beck Suicidality Ideation; ECT, Electroconvulsive Therapy; HAM-D, Hamilton Depression Rating Scale; HRDS, Hamilton Depression Rating

Scale; IDS-CR, Inventory of Depressive Symptomatology—Clinician Rated; MADRS, Montgomery-Åsberg Depression Rating Scale; MADRS-SI, Montgomery- Asberg Depression

Rating Scale; MDD, Major Depressive Disorder; MoCA, Montreal Cognitive Assessment; PHQ-9, Patient Health Questionnaire; QIDS-SR, Quick Inventory of Depressive

Symptomatology – Self-Report; SAFTEE, Systematic Assessment for Treatment Emergent Effects; TRD, Treatment Resistant Depression; WMS-RC, Wechsler Memory Scale-

Chinese Revision

Psychiatric Quarterly

Table 2 Baseline characteristics of patients in the included trials

Study Groups Duration Sample

[n]

Age [years]

[Mean/Med ia n]

Single infusion vs

multiple infusion

Dose range (mg)

Alizadeh et al., 2015 Ketamine & Propofol NA 22 34.27 ± 10.66 Multiple 0.3 mg/kg

Saline & Propofol 20 35.1 ± 12.44 0.3 mg/kg

Arabzadeh et al., 2018 Ketamine 6 weeks 41 34.31 ± 6.73 NA (oral dosage) 50 mg/day

Placebo 40 33.72 ± 8.34 50 mg/day

Burger et al., 2016 Ketamine 2 weeks 3 28 Single 0.2 mg/kg

Placebo 7 27 0.2 mg/kg

Canuso et al., 2018 Esketamine 4 weeks 35 35.7 ± 13.40 NA (intranasal) 84 mg

Placebo 31 36.0 ± 12.82 84 mg

Carspecken et al., 2018 Ketamine Ketamine = 46 weeks

Methohexital = 53 weeks

23 50 ± 12 Single 1–2mg/kg

Methohexital 27 47 ± 12 1–2mg/kg

Chen et al., 2017 Ketamine 4 weeks 63 40.94 ± 15.41 Multiple infusions 0.3 mg/kg

Control 64 37.44 ± 14.16 0.3 mg/kg

Fan et al., 2017 Ketamine 7 days 20 46.75 ± 14.04 Single 0.5 mg/kg

Midazolam 17 44.65 ± 15.1 0.5 mg/kg

Fernie et al., 2017 Ketamine One month 20 51.76 ± 9.97 Multiple infusions Up to 2 mg/kg

Propofol 20 49.88 ± 12.53 Up to 2.5 mg/kg

Gamble et al., 2018 Ketamine 4 weeks 12 42 ± 16 Single infusion vs

multiple

infusion

0.75 mg/kg

Propofol 12 46.5 ± 16 0.75 mg/kg

Ghasemi et al., 2013 Ketamine 7 days 9 35.22 ± 13.63 Multiple infusions 0.5 mg/kg

ECT 9 40 ± 16.41 0.5 mg/kg

Haile et al., 2013 Ketamine 1 week 15 48.53 ± 3.30 Single 0.5 mg/kg

Midazolam 7 42.71 ± 4.85 0.5 mg/kg

Hu et al., 2015 Ketamine 4 weeks 13 36.7 ± 14 Single infusion vs

multiple

infusion

0.5 mg/day

Placebo 1 4 4 1 ± 11.1 0.5 mg/day

Jafarinia et al., 2016 Ketamine 6 weeks 20 40.7 ± 8.71 NA 150 mg

Diclofenac 20 38.95 ± 9.22 150 mg

Ja¨rventausta K. et al.

2013

S-Ketamine 2 weeks 16 48.4 Multiple 0.4 mg/kg

Propofol & normal saline 16 53.7 0.4 mg/kg

Jiang M., et al., 2016 Ketamine 5 days 60 43.38 ± 0.95 NA 0.25–0.5 mg/kg

Control 60 41.40 ± 0.16 0.25–0.5 mg/kg

Psychiatric Quarterly

Table 2 (continued)

Study Groups Duration Sample

[n]

Age [years]

[Mean/Med ia n]

Single infusion vs

multiple infusion

Dose range (mg)

Tayyebi et al., 2018 Bolus Ketamine 2 months 25 40.84 ± 11.75 Single 0.5 mg/kg

(Bolus)

25 42.84 ± 12.17 0.75 mg/kg

(Bolus)

Infusion Ketamine 25 39 ± 11.49 0.5 mg/kg

(Infusion)

25 39.72 ± 10.18 0.75 mg/kg

(Infusion)

Lai R. et al., 2014 Ketamine 5 weeks 4 NA Multiple 01–0. 4 mg/kg

Normal saline NA

Lapidus et al., 2014 Ketamine 2 weeks 18 48.0 ± 12.8 Single Intranasal Ketamine

50 mg/day

Placebo Intranasal 0.9%

saline (Placebo)

Lenze et al., 2016 96 h infusion 8 weeks 10 44.6 ± 12.8 Single 0.6 mg/kg/h

Saline for first 95 h

and 20 min followed

by 0.5 mg/kg

Ketamine

for final 40 min

10 42.5 ± 13.8 Saline, 40-min

Ketamine at 0.5

mg/kg

Lo et al., 2016 Ketamine 7 days 11 48.5 ± 11 Multiple infusions 0.1 mg/kg - 0.5 mg/kg

Midazolam 3 0.01 mg/kg

Murrough et al., 2016 Ketamine 7 days 47 46.9 ± 12.8 Single 0.5 mg/kg

Midazolam 25 42.7 ± 11.6 Single 0.045 mg/kg

Fava et al., 2018 Ketamine 30 days 80 43.1 ± 11.9

45.5 ± 14.6

48.6 ± 12.9

47.4 ± 10.1

Single 0.1 mg/kg

0.2 mg/kg

0.5 mg/kg

1.0 mg/kg

Midazolam 19 45.6 ± 13.8 –

Daly et al., 2017 Esketamine 28, 56,

84 mg

130 days 34 44.7 [10.0] Multiple doses Esketamine 28, 56,

84 mg

Placebo 33 Placebo

Psychiatric Quarterly

Table 2 (continued)

Study Groups Duration Sample

[n]

Age [years]

[Mean/Med ia n]

Single infusion vs

multiple infusion

Dose range (mg)

Grunebaum et al., 2018 Ketamine One day 40 40.7 ± 13.1 Single infusion 0.5 mg/kg

Midazolam 40 38.4 ± 13.2 0.02 mg/kg

Kudoh et al., 2002 Gro up A Pro pofo l,

Fentanyl, Ketamine

1 week 35 46.9 ± 8.8 Single infusion 1.0 mg/kg of ketamine,

1.5 mg/kg of propofol,

and 2 □g/kg of

fentanyl

Group B Propofol,

Fentanyl

35 48.2 ± 7.4 1.5 mg/kg of propofol

and 2 □g/kg of

fentanyl

Group C Propofol,

Fentanyl, Ketamine

20 46.2 ± 10.3 1.0 mg/kg of ketamine,

1.5 mg/kg of propofol,

and 2 □g/kg of

fentanyl

Salehi et al., 2015 Ketamine 8 session 80 Not mentioned Multiple infusions 0.8 mg/kg

Sodium thiopental 80 Not mentioned 1–1.5 mg/kg

Singh et al., 2016 Ketamine 15 days 35 BID = 45.7 ± 9.6

TID = 43.3 ± 12.0

Multiple infusions 0.5 mg/kg twice daily

VS 0.5 mg/kg thrice

daily

Placebo 3 3 B ID = 40.3 ± 11.8

TID = 46.1 ± 10.5

Singh et al., 2016 Esketamine 4 days 20 0.2 mg/kg = 44.7 ± 13.38

0.4 mg/kg = 41.8 ± (11.63)

Multiple infusions 0.2, 0.4 mg/kg

Placebo 10 42.7 ± (10.89)

Sos et al., 2013 Ketamine 2 weeks 11 42.2 ± 15.1 Multiple infusions 0.5 mg/kg

Placebo 19 44.6 ± 10.9

Su et al., 2017 Ketamine 2 weeks 47 0.2 mg/kg = 45.0 ± 12.3

0.5 mg/kg = 48.5 ± 11

Single infusion 0.2, 0.5 mg/kg

Placebo 24 48.6 ± 8.2

Wang et al., 2012 Ketamine One week 16 56.2 ± 11.5 Single infusion 0.8 mg/kg

Ketamine & Propofol 16 58.6 ± 16.3

Propofol 16 53.8 ± 15.2

Xu et al., 2017 Ketamine 1 week 50 42.36 ± 7.28 Single infusion 0.5 mg/kg

Psychiatric Quarterly

Table 2 (continued)

Study Groups Duration Sample

[n]

Age [years]

[Mean/Med ia n]

Single infusion vs

multiple infusion

Dose range (mg)

Saline 43.27 ± 6.6

Xu et al., 2017 Ketamine 6 weeks 165 31 ± 4 Single infusion 0.25 mg/kg

Saline 165 32 ± 4

Yoosefi et al., 2014 Ketamine 6 ECT sessions over

2 weeks with 3 sessions every

week

16 40.87 Multiple infusions 1 to 2 mg/kg

Thiopental 15 47 2 to 3 mg/kg

Zarate et al., 2006 Ketamine One week 9 46.7 ± 11.2 Single infusion one

week a part in

cross-over study

0.5 mg/kg

Placebo 9

Study Male

[%]

Adjunct Medications (Mention the percentage

taking medications if any and what are those medications)

Common side effects Site of trial

Alizadeh et al., 2015 6 (27%) Patients were prescribed medications but names

were not mentioned.

No side effects were reported Iran

7(35%)

Arabzadeh et al., 2018 26 (63.4%) Sertraline Abdominal pain, nau sea, tremor, and

dissociation. Comparable side effects

between groups.

Iran

24 (60%)

Burger et al., 2016 2 (67%) Not mentioned No side effects were reported. USA

5(71%)

Canuso et al., 2018 13 (37.4%) Standard antidepressant started at day1, titrated

during 2 weeks and continued. If alre ady

on ADT, continued.

Nausea, dizziness, dysgeusia, dissociation,

headache, vomiting, anxiety, paresthesia,

sedation, somnolence, euphoric mood,

vertigo.

USA

10 (32%)

Carspecken et al., 2018 17 (74%) All patients received ECT sessions. Continued

use of ADTs.

Not reported. USA

24 (89%)

Chen et al., 2017 21 (33.3%) All patients receiv ed 12 ECT session

(three per week)

No diff eren ce in side effects among

both groups.

USA

23 (35.9%)

Fan et al., 2017 8 (40%) NA Not reported. China

4(23.5%)

Fernie et al., 2017 18 (45%) No restrictions were placed on the psychiatric

medications and or treatments prescribed

Not reported. Scotland

Psychiatric Quarterly

Table 2 (continued)

Study Male

[%]

Adjunct Medications (Mention the percentage

taking medications if any and what are those medications)

Common side effects Site of trial

either before or during the course of the trial.

All participated received ECT.

Gamble et al., 2018 6 (50%) All patients received 8 ECT sessions Hypertension, hypotension, nausea,

vomiting headache

Canada

6(50%)

Ghasemi et al., 2013 4 (44.4%) All patients received ECT sessions. Temporary non-significant increase

in pulse and systolic blood pressure.

Iran

444.4%)

Haile et al., 2013 Not mentioned Single dose for 40 min. Not reported. USA

Not mentioned

Hu et al., 2015 6 (46.2%) All patients received escitalopram 10 mg/day Nightmares, restlessness, dizziness,

nausea, headache and increasing salivation

China

4(28.6%)

Jafarinia et al., 2016 5 (25%) None Transient loss of appetite, blurred vision,

tremor, abdominal pain

Iran

5(25%)

Ja¨rventausta K. et al. 2013 8 (50%) Antidepressant, antipsychotic, antidepressants +

antipsychotics, benzodiazepines

Both groups received ECT treatment.

Posttreatment disorientation and

restlessness.

USA

5(31.2%)

Jiang M., et al., 2016 34 (57%) None Side effects were comparable among

both groups.

China

33 (55%)

Tayyebi et al., 2018 15 (60%) None Side effects were not repo rted. Iran

14 (56%)

11 (44%)

10 (40%)

Lai R. et al., 2014 2 (50%) Alprazolam, olanzapine, quetiapine, tranylcypromine Transient tachycardia, and hypertension. UK

Lapidus et al., 2014 10 (50%) Names of dugs not mentioned. Small increase in psychosis, dislocation,

and systolic blood pressure. Other side

effects were feeling strange, poor

memory, and weakness or fatigue.

USA

Lenze et al., 2016 2 (20%) Clonidine, SSRI , SNRI agents, aripiprazole Mild and transient side effects were

reported for blood pressure.

USA

4(40%)

Lo et al., 2016 4 (26.6%) Patients were prescribed psychotropic

medications but names were not

mentioned.

Mild depersonalization, derealization,

altered body and time perception.

Australia

Not mentioned

Psychiatric Quarterly

Table 2 (continued)

Study Male

[%]

Adjunct Medications (Mention the percentage

taking medications if any and what are those medications)

Common side effects Site of trial

Transient increase in pulse, systolic

and diastolic blood pressure.

Fatigue, light-headedness, dizziness,

blurred vision, dry mouth and emotional

liability

Murrough et al., 2016 21 (45%) Zolpid em Dizziness, blurred vision, headache, nausea

or vomiting, dry mouth, poor coordination,

poor concentration, and restlessness.

USA

14 (56%)

Fava et al., 2018 42 (52.5%) Benzodiazepine

Non- benzodiazepine hypnotics

SSRIs

SNRIs

TCAs

Bupropion

Mirtazap in e

Vortioxetine

High systolic and diastolic blood pressure

among participants in ketamine groups.

USA

8(42.1%)

Daly et al., 2017 29 (43.3%) Participants continued their existing

antidepr e s s an t treatme nt during the study

Dizziness, headache, and dissociative

symptoms

USA, Belgium

Grunebaum et al., 2018 18 (45%) Antidep res sants , anticonvulsants,

antipsychotics, benzodiazepines, lithium

(above medications were stopped at

least 24 h pre-infusion)

Four patients with suicide attempts

(3 after and 1 before study procedures),

and 3 inpatient admissions for suicidal

ideations.

Transient increase in blood pressure.

USA

14 (35%)

Kudoh et al., 2002 Not mentioned All depressed patients were medicated by

antidepressants for more than a year

Ventricular ectopic rhythm Japan

Salehi et al., 2015 37 (46.2%) Not mentioned Increased blood pressure, headache, nausea,

and fear with the illusion of awaken ing s

Iran

37 (46.2%)

Singh et al., 2016 11 (31.4%) Patients continued any antidepressant medications

they were receiving at screening, at the same

stable dosages throughout the study. The

antidepressants most commonly used (>10%

of patients in each treatment group) at baseline

Headache, anxiety, dissociation, nausea,

and dizz iness

USA

11 (31.4%)

Psychiatric Quarterly

Table 2 (continued)

Study Male

[%]

Adjunct Medications (Mention the percentage

taking medications if any and what are those medications)

Common side effects Site of trial

were fluoxetine, citalopram, and bupropion;

these agents were continued throughout the study.

Singh et al., 2016 8 (40%) Not mentioned The most common side effects were nausea

and headache for Esketamine 0.2 mg/kg

and headache, dissociation , and nau sea

for Esketamine 0.40 mg/kg.

Belgium, Germany, Poland

4(40%)

Sos et al., 2013 5 (45.5%) Dissociation, perceptual disturbances,

confusion, mild increases in blood

pressure, emotional blunting and

euphoria.

Czech Republic

10 (52.6%)

Su et al., 2017 9 (19.1%) Not mentioned Increased in systolic blood pressure Taiwan

9(37.5%)

Wang et al., 2012 6 (50%) SSRI, TCA, Atypical antipsychotics,

Benzodiazep ine s

Hypertension during the ECT session,

angialgia at the site of injection of

the anesthetic and sense of fear upon

awakening from anesthesia

USA

7(58%)

5(42%)

Xu et al., 2017 0 Not reported Not reported. China

Xu et al., 2017 0 Single Dizziness, drowsiness, diplopia,

hallucinations, headache, and

vomiting

China

Yoosefi et al., 2014 7 (50%) Not mentioned Increase in BP 10 min after induction

among Ketamine group

Iran

8(53.3%)

Zarate et al., 2006 0 Participants did not receive these

medications during the length of study.

Perceptual disturbances, confusion,

elevations in blood pressure,

euphoria, dizziness, and increased libido

USA

ADT, antidepressant treatment, ECT-Electroconvulsive therapy; NA, Not Applicable; SNRI, Selective Norepinephrine Re-Uptake Inhibitor; SSRI, Selective Serotonin Re-Uptake

Inhibitor

Psychiatric Quarterly

Target Population

In this review article, 35 studies were assessed for effectiveness in treating clinical depression,

while Ketamine was used for the prevention of postpartum depression in one study [18]. The

inclusion criterion was TRD (n = 13) and moderate to severe MDD (n = 22). Ketamine was

also used as anesthetic and antidepressant in participants who underwent orthopedic surgery

and unilateral mastectomy [27,28]. In one study, participants were newly diagnosed with

breast cancer [29]. Another study focused on prevention of depression in pregnant patients

undergoing elective cesarean section [26].

Scales for Outcome Measures

The primary outcome was measured using various rating scales. The breakdown of these

measure was: Hamilton Depression Rating Scale (HDRS) (n = 22), Montgomery–Åsberg

Depression Rating Scale (MADRS) (n = 18), Beck Depression Inventory (BDI) (n =5), and

Patient Health Questionnaire (PHQ) - 9 (n =3).

Dose of Ketamine

In 32 studies, Ketamine was used in the treatment arm whereas three studies used

Esketamine as the active agent. It was administered as Intravenous (IV) infusion in 30

studies, intranasal in two studies, a nd orally in three studies. One study administered

Ketamine through a subcutaneous route. Intravenous Ketamine was used in varying

dosages ranging from 0.1 mg/kg to 1 mg/kg day in 29 studies. Three studies used a dose

range of up to 2 mg/kg. Intranasal Ketamine was administered between dose ranges of 28

to84mg.DosageoforalKetaminerangedfrom50mg/dayto50mgthreetimesaday.

Studies comparing the dose-d ependent response found a greater response at doses o f

0.5 mg/kg to 1 mg/kg IV Ketmaine [24,30,31] whereas Singh et al., 2016 found similar

response for doses of 0.2 mg/kg and 0.4 mg/kg [17].

Change in Depression and Related Outcome Measures

IV Ketamine was used in 27 studies, with 19 studies reporting significant improvement

compared to the control or placebo group of participants with MDD. One study com-

paring Ketamine at 0.5 mg/kg to ECT reported similar improvement among both g roups

[32]. However, the antidepressant benefits lasted up to 72 h on BDI scale and one week

on HDRS scale after the last infusion of Ketamine. Among studies with favorable

responses, two studies used Ketamine as an anesthetic agent in patients receiving ECT

treatments. Eight studies reported lack of improvement with Ketamine compared to the

control gro up. In six of th ese studies, Ketamine was used as an antidepressant in patients

receiving ECT treatment [15,33–37]. Common reasons for lack of efficiency were cited

as ECT ceiling treatment effect and ECT blunting the response to Ketamine. Other

reasons include inadequate sample size [38], trauma from breast cancer and surgical

treatment of breast cancer [26]. It is noteworthy that Ketamine resulted in faster im-

provement [36]. Intravenous Ketamine was ineffective for prevention of postpartum

depression [18].

Psychiatric Quarterly

Intranasal Ketamine was administered in two studies at doses of 50 mg [39]and 84 mg [40]

with improvement in both studies. Oral Ketamine at doses of 50 mg/day [41] and 50 mg three

times a day [42] reporting significant improvement in both studies. Loo and colleagues (2016)

compared Ketamine administered intravenously, intramuscularly, and subcutaneously to the

control group. About 75% of patients with IV Ketamine, 60% with IM Ketamine, and 100%

with SC Ketamine reported improvement in depression scores [9].

In a study, an increase in BDNF level after administration of Ketamine had a negative

correlation with depression [43]. Similar results were reported in a study comparing Ketamine

and ECT to ECT and methohexital group, indicating BDNF as a potential biomarker for

antidepressant response [31]. However, BDNF genotype was not indicated as a predictor of

response.

Side Effects

No side effects were reported in nine RCTs. The most common side effects were fatigue,

nausea, vomiting, transient increase in blood pressure, anxiety, confusion, dissociation, dizzi-

ness, and drowsiness. Other side effects were diplopia, emotional blunting, euphoria, head-

ache, increased libido, perceptual disturbances, paraesthesia, sedation, and vertigo. Ventricular

ectopic rhythm was reported in one study [28]. One study reported suicidal ideations and

attempt [10].

Quality Assessment of RCTs

Random sequence generation was at low risk among 26 studies and allocation concealment

among 26 RCTs. Frequency of studies reporting a low risk across other domains of Cochrane

risk of bias tool was: blinding of outcome assessors (n = 30), blinding of participants and

personnel (n = 27), attrition bias (n = 27), other sources of bias (n = 30), and selective reporting

(n = 34). A total of 10 studies were rated as having a high risk of overall bias i.e. ≥ 3 matrices

of risk of bias tool were rated as having unclear or high risk of bias for these studies. Figure 2.

presents a clustered bar chart exhibiting frequencies of high, unclear and low risk bias across

all matrices of Cochrane risk of bias tool. Figure 3. presents study-wise risk of bias across all

matrices of Cochrane risk of bias tool.

Fig. 2 Risk of Bias Graph

Psychiatric Quarterly

Fig. 3 Risk of Bias Summary

Psychiatric Quarterly

Discussion

This systematic review provides a comprehensive overview of the use of Ketamine in MDD

with chronic and treatment-resistant course. Overall, twenty-six studies (77%) reported sig-

nificant improvement in depressive symptoms among patients receiving Ketamine compared

to the control group. Of the remaining eight studies, participants received ECT in five studies

in both the treatment and control group. Oral and intranasal Ketamine were effective in two

and three studies, respectively. It is noteworthy that one study comparing ECT to Ketamine

reported similar improvement in both groups [32]. However, Ketamine was not found to be

effective for the prevention of postpartum depression [18]. Ketamine was associated with

higher BDNF levels in patients with MDD compared to the control group and this higher

BDNF had a negative correlation with depression scores [31,43].

In the majority of studies (21/30), IV Ketamine was effective for treatment of unipolar

depression and ineffective in prevention of postpartum depression in one study [18]. The

existing literature suggests that Ketamine is superior to placebo and is equally effective as ECT

[32]. It resulted in significantly higher rates of remission with odd ratio (OR) of ≥3.86 and

Number Needed to Treat (NNT) of ≤6 after 24 h, 3 days and 7 days [44]. The clinical response

for Ketamine was reported at OR of ≥4.87 and NNT of ≤4[44]. The clinical applicability of

Ketamine is limited by shorter duration of action that can be challenging in patients with

chronic and treatment- resistant depression. The existing evidence suggests that the clinical

response is observable in 40 to 120 min in about 50% of patients. However, this response

lasted for two hours (51.1% Ketamine group VS 2% control group), one day (52.6% Ketamine

group VS 7% control group), three days (46.6% Ketamine group VS 7.1% control group), and

seven days (31% Ketamine group VS 7% control group) according to a pooled analysis of

seven RCTs [45]. The odds ratio for treatment response was clinically significant at day seven

with Ketamine in patients with unipolar depression [45]. The effects of Ketamine dissipated at

day 14, with only 10.9% responding to Ketamine compared to the control group [45].

Due to the chronic course of depression, the role of Ketamine was evaluated in the context

of multiple infusions of Ketamine. In this review, 13 studies administered multiple infusions of

IV Ketamine with improvement in six studies. Out of the remaining seven studies with no

significant benefits for Ketamine group, participants received ECT in addition to IV Ketamine

in five studies. The results posit discussion of two clinical questions: Ketamine as a potent

antidepressant option in combination with ECT and efficacy of multiple infusions of IV

Ketamine.

The lack of effectiveness of Ketamine in combination with ECT can be attributed to ECT

treatment ceiling and blunting of response [37]. A meta-analysis reported that Ketamine

augmentation of ECT resulted in a significantly greater reduction in depressive symptoms at

first treatment, but this efficacy did not last throughout the complete course of ECT treatments

[45]. This was in contrast to another meta-analysis reporting no additional benefit of Ketamine

when used along with ECT [46]. Considering small to moderate benefits with this combination

[47], Kellner and Iosifescu opined that this small -to-moderate effect size in patients with

chronic and TRD is worth investigating [48]. The existing scientific evidence lacks definitive,

adequately designed and well-powered studies in pursuit of this clinical question [48].

In this review article, Ghasemi and colleagues reported that multiple infusions of low dose

Ketamine (0.5 mg/kg, three times on three test days) were equally effective in improving

depression scores compared to ECT [32]. This effect was observable at 72 h and one week

after the last/third injection of Ketamine on BDI and HDRS scales. It is exciting to note the

Psychiatric Quarterly

Ketamine resulted in faster and more rapid improvement in earlier stages of treatment. These

results should be carefully considered in the context of smaller sample size and titration

method for ECT, possibly affecting the efficacy of ECT early in the course of treatment.

While it is a positive finding, it should be explored in studies of optimal sample size and robust

study design [32].

Ketamine was effective in five studies, when administered orally (two studies) and intra-

nasally (three studies). Oral Ketamine is suggested to exert significant antidepressant effect

with lesser risk of side effects but a slower pace of action than IV Ketamine. This conclusion

was drawn from a systematic review of two RCTs, one open-label trial, five retrospective chart

reviews, and five case reports.

Also, Esketamine, a nasal spray, was approved by the Food and Drug Administration

(FDA) for unipolar depression in March 2019 [49]. The recommended dose range for

Esketamine is 56 mg or 84 mg during induction phase (week 1 and 4) and maintenance phase

(week five to long-term) [50].

Ketamine antidepressant efficacy is determined by different variables such as route of

administration and dosage [51]. The most frequently prescribed dose of IV Ketamine is

0.5 mg/kg; however, some patients respond to dose range of 0.1 mg/kg to 0.75 mg/kg [51].

Higher doses are associated with greater risk of undesirable effects. The effectiveness of

Ketamine is also evident by oral, sublingual, transmucosal, intranasal, intravenous, intramus-

cular, and subcutaneous routes [51].

The most common side effects associated with ketamine are nausea, vomiting, dizziness,

diplopia, drowsiness, dysphoria, hallucinations, and confusion. Ketamine can cause delirium

in about 6% to 12% of patients [51]. Patients receiving Ketamine require close monitoring of

vital signs and cardiac status. It is also essential to monitor for neuropsychiatric functioning in

the clinic for return to baseline function [52].

This systematic review has several strengths. An electronic search of academic databases

combined with manual searching for references provides an exhaustive search for relevant

evidence. It provides an overview of RCTs of Ketamine in comparison to other treatment

options. However, this review also has several limitations. Due to heterogeneity, a meta-

analysis could not be performed. It is also important to consider the higher risk of bias in 10

studies while interpreting the results of these studies.

Conclusion

Ketamine is an effective treatment option for patients with MDD with considerable adverse

when administered via IV, IN and oral routes. The dose range for IV Ketamine ranges between

0.5 mg/kg to 1 mg/kg, 28–84 mg for IN dose, and oral dose ranging from 50 mg daily to three

times a day. It is noteworthy that Ketamine was equally effective compared to ECT with a

faster response among patients who received Ketamine. Ketamine argumentation of ECT

needs to be explored further in well-designed studies of adequate sample size. The short-lived

antidepressant effect of Ketamine is a potential limitation, needing further studies administer-

ing multiple infusions.

Compliance with Ethical Standards

Disclosure of Potential Conflicts of Interest None to report.

Psychiatric Quarterly

Research Involving Human Participants and/or Animals Not applicable since it is a review article.

Informed Consent Not applicable since it is a review article.

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institutional affiliations.

Psychiatric Quarterly

Raheel Imtiaz Memon, M.D., is a second-year psychiatry resident at Henry Ford Allegiance Health, Jackson,

Michigan. He did his medical school from Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan.

He is interested in pursuing a career in child and adolescent psychiatry with a particular focus on

neurodevelopmental disorders, specifically autism spectrum disorder, and the impact of substances and trauma

during childhood. He will be applying for child and adolescent psychiatry fellowship after completion of general

psychiatry residency and planning to stay in academia later on.

Sadiq Naveed, M.D., is an assistant professor in the Department of Psychiatry and Behavioral Sciences at the

University of Kansas Medical Center. He is boardcertified in child and adolescent psychiatry, as well as adult

psychiatry. He also completed Master of Public Health degree from Benedictine University in Illinois. He earned

his medical degree from Nishtar Medical College in Multan, Pakistan, and received his training in adult

psychiatry at Griffin Memorial Hospital in Norman, Oklahoma. He also completed his training in child and

adolescent psychiatry at the University of Kansas Medical Center. Dr. Sadiq Naveed is Honorary Research

Fellow at Human Development Research Foundation of Pakistan. He is also completing his postgraduate course

in University of Massachusetts, Boston.

Amber Ehsan Faquih, M.D., graduated from Dow University of Health Sciences, Karachi, Pakistan. Presently,

she is working as research assistant and working on different projects. She is aspiring residency applicant and

keenly interested in pursuing her career in psychiatry.

Ania Fida graduated from King Edward Medical University, started Psychiatry Residency in Pakistan then

moved to the US. Since then, she has engaged in clinical rotation and also have worked as a research assistant.

She will be starting her Psychiatry Residency Training at Medical College of Wisconsin Central Wausau in July

2020.

Noureen Abbas, MD, graduated from Fatima Memorial Hospital College of Medicine & Dentistry. She is

currently working as a research assistant. She will be starting a residency physician at Cahaba- University of

Alabama at Birmingham in July 2020.

Amna Mohyud Din Chaudhary, M.D., is a graduate of Nishtar Medical College and Hospital, Multan,

Pakistan. She is primarily interested in psychiatry and a general psychiatry residency aspirant. Her interests

include mood disorder, and schizophrenia.

Zheala Qayyum, MD. MMSc is the Assistant Clinical Professor of Psychiatry at Yale School of Medicine. She

is board certified in general psychiatry, child and adolescent psychiatry and consultation liaison psychiatry. She

also completed her Master of Medical Science in Medical Education from Harvard Medical School. She is

currently the Program Director for the Child and Adolescent psychiatry fellowship at Boston Children’s Hospital

and faculty at Harvard Medical School. Her interests included early onset psychosis, supporting mental health of

LGBTQ youth, psychoncology and palliative care in children and adolescents. Additionally, her research

interests lie in the supervision of trainees in the event of patient death by suicide.

Psychiatric Quarterly

Affiliations

Raheel Imtiaz Memon

& Sadiq Naveed

& Amber Ehsan Faquih

& Ania Fida

& Noureen

Abbas

& Amna Mohyud Din Chaudhary

& Zheala Qayyum

Raheel Imtiaz Memon

RMEMON2@HFHS.ORG

Amber Ehsan Faquih

amber_jawed17@live.com

Ania Fida

an.fida@hotmail.com

Noureen Abbas

noureenabbasmd@gmail.com

Amna Mohyud Din Chaudhary

dramna2014@gmail.com

Zheala Qayyum

zheala.qayyum@childrens.harvard.edu

Resident Physician, Henry Ford Allegiance Health, Jackson, MI, USA

University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, USA

Dow University of Health Sciences, Karachi, Pakistan

King Edward Medical University, Lahore, Pakistan

FMH College of Medicine & Dentistry, Lahore, Pakistan

Nishtar Medical University, Multan, Pakistan

Boston Children’s Hospital, Boston, MA, USA

Psychiatric Quarterly