Effectiveness and Safety of Ketamine for Unipolar ...
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Henry Ford Health System Henry Ford Health System Henry Ford Health System Scholarly Commons Henry Ford Health System Scholarly Commons 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 System, [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. This Article is brought to you for free and open access by the Behavioral Health Services / Psychiatry at Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Behavioral Health Articles by an authorized administrator of Henry Ford Health System Scholarly Commons.
Transcript of Effectiveness and Safety of Ketamine for Unipolar ...
Henry Ford Health System Henry Ford Health System
Henry Ford Health System Scholarly Commons Henry Ford Health System Scholarly Commons
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 System, [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.
This Article is brought to you for free and open access by the Behavioral Health Services / Psychiatry at Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Behavioral Health Articles by an authorized administrator of Henry Ford Health System Scholarly Commons.
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 System Scholarly Commons: https://scholarlycommons.henryford.com/behavioralhealth_articles/83
REVIEW ARTICLE
Effectiveness and Safety of Ketamine for UnipolarDepression: a Systematic Review
Raheel Imtiaz Memon1 & Sadiq Naveed2 & Amber Ehsan Faquih3 & Ania Fida4 &
Noureen Abbas5 & Amna Mohyud Din Chaudhary6 & Zheala Qayyum7
# Springer Science+Business Media, LLC, part of Springer Nature 2020
AbstractMajor 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 inpatients with MDD. This systematic review was conducted following the guidelines ofPreferred 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 eligibilitycriteria, 35 randomized controlled trials (RCTs) were included. Quality assessment ofincluded studies was done by using the Cochrane risk-of-bias tool for RCTs. Thirty-fiveRCTs 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 includedstudies 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 duringelectroconvulsive 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 effectswhen administered via oral, IV and IN routes. Ketamine agumentation of ECT requiresfurther exploration in well-designed studies with adequate sample size. The short-livedantidepressant effect of Ketamine is a potential limitation, therefore, further studiesadministering multiple infusions for acute treatment and maintenance are necessary.
Keywords Ketamine .MDD .Major depressivedisorder .MDD .Treatment-resistant depression
Psychiatric Quarterlyhttps://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 [email protected]
Extended author information available on the last page of the article
Introduction
Major Depressive Disorder (MDD) is a widespread and disabling illness with a lifetimeprevalence 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 ofdepression has increased by 49.86% in the last two decades and it is estimated that MDD willbecome 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 ofrecurrence 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, and50% to workplace costs [5]. Beside the financial implications, around 90% of suicidal patientshave an underlying psychiatric illness with MDD being the top of the list [6] and about 2–15%of patients with MDD complete suicide [7].
The treatment of depression requires several careful considerations, such as MDD withsuicidal behaviors, early-onset depression, chronic depression, and treatment- resistant depres-sion. With an increased emphasis on deinstitutionalization, there is a policy shift to managepatients in a less restrictive environment with shortened length of hospital stays [8]. In thiscontext, pharmacological options with robust and faster response became critically importantin treatment of patients with MDD. Existing treatment options such as antidepressants,psychotherapy, and electroconvulsive therapy (ECT) are effective but come at the cost of timelag, so a large number of patients face the challenge of suicidal thoughts and impairingdepressive symptoms for weeks after initiation of treatment [9].
More importantly, treatment- resistant depression (TRD) continues to be a significantpublic health issue. Despite multiple treatment regimens, about 60–70% of patients withMDD respond to first-line antidepressants, whereas about one-third of patients struggle withdebilitating and chronic depression [2]. Recently, in addition to psychopharmacologicaltreatments 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, hasantidepressant 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 receptorantagonist, was first approved in 1970 for anesthesia. It is also used during ECT since it canintrinsically increase the seizure duration with minimal cognitive deficits [2,10,11]. The use ofKetamine has recently expanded to its antidepressant use at sub-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 neurotrophicfactor (BDNF). BDNF, a neurotrophic factor, is involved in neuronal maturation,neurogenesis, and synaptic plasticity [15]. Ketamine is a racemate compound of 2 enantio-mers: R-(2)-ketamine enantiomer (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 antidepressantaction is reported to last for a week. This raises an important cue that its action is not entirelydependent 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 theprevention and treatment of unipolar depression.
Methods
This systematic review was conducted according to the guidelines of the Preferred ReportingItems for Systematic Reviews and Meta-Analysis (PRISMA) checklist (SupplementaryTable 1). The protocol was developed in March 2019 and was registered with the InternationalProspective 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 withketamine as a pharmacotherapy.
2. RCTs that focused on the adult population with MDD were included, who were eitherscreened for depression using validated screening instruments or diagnostic systems (suchas International Statistical Classification of Diseases and Related Health Problems orDiagnostic and Statistical Manual).
– No restriction on race, geography, sex, age, ethnicity, or language and publicationdate were applied.
The exclusion criteria were:
1. Study design other than RCT (observational study, case reports, case series, letter toeditors, study protocols, thesis, reviews, commentary, conference papers, book chapter ornews articles).
2. Studies discussing the role of Ketamine for bipolar depression or diagnosis other thanMDD.
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, Cochraneclinical trials registry, Web of Science, PsycINFO, POPLINE, Global Health Library,and Virtual Health Library through September 2018, using the following searchstrategy: (ketamine) AND (trial OR RCT OR Clinical-trial) AND (depressive ORdepression OR “depressive-disorder”). The manual search of references and relevantarticles for included studies was performed by two independent reviewers. Anydiscrepancies among reviewers were resolved by discussion or guidance from a seniorreviewer (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 abstractscreening (when available) followed by the full-text screening of the included articles by usingthe predetermined eligibility criteria. Disagreements were resolved by discussion amongreviewers or guidance from a senior reviewer (SN).
Data Extraction
The data were extracted by two independent reviewers and cross-checked for accuracy bythe senior author (SN). The name of authors, sample size, site of the trial, participantcharacteristics, route of administration, dose range, clinical outcomes, the adjunct treat-ment used, and common side effects were tabulated. The meta-analysis was not performeddue to varying study design, population of interest, and treatment outcomes, posingpotential heterogeneity.
Risk of Bias Assessment
Two authors assessed the quality of the studies without blinding to authorship or journal, usingthe Cochrane tool for randomized controlled trials against several matrices: a) sequencegeneration, b) allocation concealment, c) blinding of participants and personnel, d) blindingof 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 referencespredicated on their titles and abstracts screening. After the application of inclusion andexclusion criteria, 581 citations were excluded after title and abstract screening. Later thoroughscreening of 108 full texts eventually yielded 35 RCTs. Fig. 1, PRISMA Flow Diagramsummarizes the screening process.
Study Characteristics
This review article includes 35 RCTs conducted between 2002 to 2018, with most of the studysites in the USA [14], Iran [9], and China (4) [19–23]. The remaining trials were singularlyconducted 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 studyin Belgium, Germany, and Poland. There were 2183 participants in these studies with an agerange 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 inwomen [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
Table1
Overview
ofrandom
ized
controlledtrialsincluded
inthemeta-analysis
Study
Design
InclusionCriteria
Prim
aryOutcome
SecondaryOutcome
Alizadeh
etal.,
2015
Propofol
&Ketam
inevs
Propofol
&placebo
Age
18–65,
sufferingfrom
MDD,and
HDRSscoreof
≥20
MeanHDRSscores
Not
mentio
ned
Arabzadeh
etal.,
2018
Sertralin
e&
Ketam
inevs
Sertralin
e&
placebo
Age
18–60,
patientswith
moderateto
severe
depression,H
DRS
score≥20
Changein
theHDRSscorefrom
baselin
eto
week2across
thetwo
groups.
1)DifferenceintheHDRSscoreatweek4
and6.
2)Differencein
earlyim
provem
ent(≥
20%
reductionin
HDRSscorewith
inthefirsttwoweeks)
3)Responseto
treatm
ent(≥5
0%reduction
intheHDRSscoreattheterm
inationof
thetrial)
4)Rem
ission
(HDRSscore≤7atthe
term
inationof
thetrial)betweenthetwo
groups.
Burgeretal.,2016
Singleinfusion
ofKetam
inevs
placebo
Age
18–65years,BeckSu
icidality
Scale(BSS
)score>4,
BeckHope-
lessness
Scale(BHS)
score>8,
BeckDepressionInventoryscore>
19,and
theability
togive
inform
edconsent.Negativepregnancytest
forfemales.
BeckSu
icidality
Scale(BSS
)BeckHopeless-ness
Scale(BHS)
Canusoetal.,
2018
Esketam
inevs
Placebo
Age
19–64,
sufferingfrom
MDD
with
outpsychotic
features,and
ascore>/=22
onthe
Montgom
ery-ÅsbergDepression
RatingScale(M
ADRS).
1)Changein
Montgom
ery-Åsberg
DepressionRatingScale(M
ADRS)
scorefrom
baselin
eto
4hafter
initialdose.
2)Clin
icianglobaljudgmentofsuicide
risk
(from
theSu
icideIdeatio
nand
BehaviorAssessm
entTool).
The
prim
aryoutcom
emeasuresat24
handdouble-blindendpoint
atday25.
Carspeckenetal.,
2018
Ketam
inevs
Methohexital
Allveterans
>18
yearsof
age,
scheduledforan
indexcourse
ofECTforTRD
PHQ-9,H
AM-D
MOCA
Chenetal.,2017
Ketam
inevs
propofol
Age
18–65,
with
MDD,H
AM-D
,scores
>35.
Long-term
mem
ory,
short-term
mem
ory,
andim
mediatemem
ory
wereassessed
forallpatientsusing
Depressionwas
assessed
bythe24-item
HAM-D
interview
Psychiatric Quarterly
Table1
(contin
ued)
Study
Design
InclusionCriteria
Prim
aryOutcome
SecondaryOutcome
theWechslerMem
ory
Scale-Chinese
Revision(W
MS-RC)
Fanetal.,2017
Ketam
inevs
Midazolam
Participantswith
MDD
andnewly
diagnosedbreastcancer
(A)Su
icidalideatio
nseverity
evaluatedwith
BSI
score.
(B)Su
icidalideatio
nseverity
evaluatedwith
MADRS-SI
Score.
(C)Overalldepression
severity
evaluatedwith
MADRSscore
Not
mentio
ned
Gam
bleetal.,
2018
Ketam
inevs
Propofol
Age
>17,T
RD,M
ADRSscoreof
20.
Num
berof
ECTtreatm
entsrequired
toreacha50%
reductionin
baselin
eMADRS
1.Changein
CADSS
2.Changein
ALS-18
3.Changein
ECTenergy
settingsand
seizurequality
4.Hem
odynam
icinstability
and
respiratorycomplications
5.Tim
eto
discharge
6.Changein
MADRSscore24
hafter
each
treatm
entand30
days
afterfinal
treatm
entforan
expected
averageof
2months
7.The
numberof
ECTsessions
required
toachievedepression
remission
(MADRS
≤10)
8.The
proportionof
depressedpatients
(MADRS>20)at30
days
afterthelast
ECTsession
9.Changein
systolicbloodpressure
Ghasemietal.,
2013
Ketam
inevs
ECT
Participantswith
MDD,ages
18–75years,with
acurrentmajor
depressive
episode.
HDRS,
BDIatbaselin
e,24
hafter
each
treatm
ent,72
handoneweek
afterthelast(third)
Ketam
ineor
ECT.
Not
mentio
ned
Haileetal.,2013
Ketam
inevs
Midazolam
Age
21–80years,participantswith
TRD,currentepisodeof
depression.
Not
mentio
ned
Psychiatric Quarterly
Table1
(contin
ued)
Study
Design
InclusionCriteria
Prim
aryOutcome
SecondaryOutcome
Response=50%
orgreaterreduction
inMADRSscorecomparedto
baselin
eat7daypost-infusion
Huetal.,2015
Ketam
inevs
Placebo
Age
18–60years,patientswith
TRD,
≥24
onHAM-D
Response=≥50%
reductionin
baselin
eMADRSscores.
Rem
ission
=MADRStotalscore≤10
-Proportio
nof
respondersandremittersin
each
group
-Severity
ofinvestigator-rated
depressive
symptom
s(M
ADRS)
-Self-rated
scores
onQuick
Inventoryof
DepressiveSy
mptom
atology–
Self-Report(Q
IDS-SR
)–Chinese
version,
-Su
icidalideatio
n(Q
IDS-SR
item
12)
-Side-effectsandseverity
ofmanic,p
sy-
choticanddissociativ
esymptom
s.Jafariniaetal.,
2016
Ketam
inevs
Diclofenac
Age
20–55years,patientswith
TRD,
chronicmild
-moderateheadache
HDRSatweek3and6,
HADS
Com
parisonof
changesin
HDRSscores
from
baselin
eto
each
timepoint,
response
totreatm
ent(defined
as≥5
0%reductionin
theHDRSscore),
remission
(defined
asHRDSscore≤7),
andseverity
ofpain
intensity
between
thetreatm
entgroups
andevaluationof
theantidepressanteffectsof
each
drug
separately.
JarventaustaK.
etal.2
013
S-Ketam
ine&
propofol
vsNormal
salin
e&
propofol
Age
18–80years,participantswith
TRD
with
failure
oftwo
antidepressantsin
thepast.
MADRS
Not
mentio
ned
JiangM.,etal.,
2016
Ketam
inevs
Control
Age
18–60years,patientsundergoing
orthopedicsurgery
PHQ-9
Not
mentio
ned
Tayyebi
etal.,
2018
Ketam
inebolusvs
infusion
Age
20–60years,patientswith
MDD
HDRS,
BDI
Not
mentio
ned
LaiR.etal.,
2014
Ketam
ineatdifferentdosesvs
salin
eParticipantswith
TRD,A
ge29–66years,MADRSscoreof
≥□2
0
MADRS
SAFT
EEscale
Psychiatric Quarterly
Table1
(contin
ued)
Study
Design
InclusionCriteria
Prim
aryOutcome
SecondaryOutcome
Lapidus
etal.,
2014
Ketam
inevs
Placebo
Age
21–65years,MDD,b
aseline
scoreof
≥30on
theInventoryof
Depressive
Symptom
atology—
Clin
icianRated
(IDS-C)
MADRSat24
haftertreatm
ent
System
aticAssessm
entforTreatment
Emergent
Effects(SAFT
EE)
Lenze
etal.,2016
Salin
einfusion
followed
byKetam
ine
40min
infusion
vs96
hinfusion
Age
18–65years,MDD,M
ADRS
scoreof
≥MADRS
Not
mentio
ned
Loetal.,2016
Ketam
inevs
Midazolam
Participants,ages≥1
8years,major
depressive
disorderandadepressive
episodeof
duration≥4
weeks.
Changein
MADRSscores
BPR
S,YMRS,
CADSS
Murroughetal.,
2016
Ketam
inevs
Midazolam
Age
21–80,
with
MDD,and
inadequateresponse
toatleastthree
therapeutic
trialsof
anantidepressant
Changein
MADRSscores
24hafter
infusion
MADRSresponse
rate,changeinscoreon
theQuick
Inventoryof
Depressive
Symptom
atology—
Self-Report,scores
ontheClin
icalGlobalImpression
(CGI)
severity
andim
provem
entmeasures,
anddurabilityof
benefitforup
to7days
follo
winginfusion.
Fava
etal.,2018
Ketam
inevs
Midazolam
Age
18–70yearsoldpatientwith
TRD
MDD,current
major
depressive
ep-
isode
HAM-D
-62-
groups
comparison=Ketam
inevs
Midazolam
5-groups
comparisonbetweenallfour
dosesof
Ketam
ineandplacebo
MADRS,
CGI-S,
CGI-I,SD
Q,and
PAS
Fernieetal.,2017
Ketam
inevs
Propofol
Age
18–70yearswith
MDDreceiving
ECTon
aninform
albasis,consid-
ered
fitby
ananesthetist,hadno
comorbidpsychiatricdiagnoses
HRSD
,MADRS
Cognitiv
efunction,
assessed
before
ECT
usingtheCam
bridge
Autom
ated
NeuropsychologicalTestBattery
Spatial
Recognitio
nMem
orytask
(CANTAB
SRM)
Dalyetal.,2017
Esketam
inevs
Placebo
Age
20–64years,TRDMDDandID
Sscore≥34
Changein
MADRS
Clin
icalGlobalIm
pression
ofSeverity
scale
Severity
ofanxietyon
theGeneralized
Anxiety
Disorder7-item
scale
Psychiatric Quarterly
Table1
(contin
ued)
Study
Design
InclusionCriteria
Prim
aryOutcome
SecondaryOutcome
Grunebaum
etal.,
2018
Ketam
inevs
Midazolam
18to
65years,adultswith
current
MDD,H
DRS-17
score≥16
and
score≥4on
theScaleforSu
icidal
Ideatio
n(SSI)
SSI
Differentialchangebetweengroups
inSS
Ianddepressive
symptom
s(H
DRS1
7and24,B
DI,PO
MS)
Kudoh
etal.,2002
Propofol,F
entanyl,Ketam
inevs
Propofol
andFentanyl
Participants,ages35
to63
yearsfor
interventio
ngroupand30
to64
yearsforcontrolgroup),all
patientswith
MDD,u
ndergoing
orthopedicsurgery.
The
controlgroupdidnothave
any
psychiatricillnesses.
Changein
HDRSscores
Postoperativeconfusionassessed
using
confusionassessmentmethod(CAM),
pain
was
estim
ated
usinga100mm
visualanalog
scale
Salehi
etal.,2015
Ketam
inevs
Sodium
thiopental
Age
20and60-year-old,
TRD
HMDRS
Blood
pressure
Singhetal.,2016
Ketam
inevs
Placebo
18–64yearsoldadults,recurrent
MDD-TRwith
outpsychotic
features,and
ascoreof
34on
the
30-item
Inventoryof
Depressive
Symptom
atology–Clinicianrated.
Changein
MADRSscores
Early
onsetof
clinicalresponse,total
numberof
respondersatday15,
total
ChangeinMADRSscorefrom
baseline
throughday29,C
linicalGlobal
Impressionsseverity
score(CGI-S),
CGIim
provem
entscore(CGI-I),
Patient
GlobalIm
pression
severity
score(PGI-S),P
atient
Global
Impression
ofChangescore(PGI-C)
Singhetal.,2016
Esketam
inevs
Placebo
18–64yearsoldadults,recurrent
MDD-TRwith
outpsychotic
fea-
tures.
Changein
MADRSscores
24h.
change
inMADRStotalscorefrom
day1
today3andday4andfrom
day4to
day7,
change
inMADRStotalscore
from
day1to
day35,changein
the
Quick
Inventoryof
Depressive
Symptom
atology–SelfReport,Clin
ical
GlobalIm
pression–S
everity
,Clin
ical
GlobalIm
pression–Improvem
ent,Pa-
tientGlobalImpression
ofSeverity,and
Patient
GlobalIm
pression
ofChange.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Design
InclusionCriteria
Prim
aryOutcome
SecondaryOutcome
Sosetal.,2013
Ketam
inevs
Placebo
Participantswith
MDD,ages18and
65yearsold,
MADRSscoreof
20MADRSscorechange
atday1,
4and
7betweenketamineandplacebo
Responserates
Plasmalevelsof
ketamineandits
metabolite
nor-ketamineduring
keta-
mineandplaceboinfusion
atbaselin
e,10
mins,30
minsof
theinfusion)
Suetal.,2017
Ketam
inevs
Placebo
Allpatientswith
Treatment-resistance
MDD,score
ofmorethan
18on
HAMD
HAMD-17scores
Responserate,d
osegroupResponder
vsBDNFgenotype,P
redictor
ofresponse
andsustainedeffect
Wangetal.,2012
Ketam
inevs
Propofol
vsKetam
ine
&Propofol
Patient
with
MDD
andscore≥20
onHDRS.
Changein
HDRSscale
Nonementio
ned
Xuetal.,2017
Ketam
inevs
Control
Wom
enagebetween30
and35
years,
who
underw
entmodifiedradical
mastectom
yof
unilateralbreast.
HAMD
scoreof
≥17.
Changein
HAMD
scores
Not
mentio
ned
Xuetal.,2017
Ketam
inevs
Salin
eAmerican
Societyof
Anesthesiologists
(ASA
)grade1–2andelectivecae-
sarean
deliverywith
spinal
anaethesia.
Forpreventio
nof
depression
EPD
SNum
ericratin
gscalescoreof
pain
Yoosefietal.,
2014
Ketam
inevs
Thiopental
20–50yearsold,
MDD
and
HAM-D
≥18.
Meanchange
inHAM-D
scores
The
effectsof
ketamineandthiopentalon
thecognitive
consequences,seizure
parameters,andhemodynam
icfactors
ofECT
Zarateetal.,2006
Ketam
inevs
Placebo
Participantswith
treatm
ent-resistant
MDD,ages18–65yearsold,
HDRSscoreof
≥18.
Meanchange
inHDRS-21
scores
BeckDepressionInventory(BDI),B
rief
PsychiatricRatingScale(BPRS)
posi-
tivesymptom
ssubscale,Y
oung
Mania
RatingScale(Y
MRS).
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Alizadeh
etal.,
2015
IVKetam
ine0.3mg/kg
per
ECTsession
5mlof
norm
alsalin
ePrimary:
MeanHDRSscores
Baselinescores
The
HDRSscores
weresimilaram
ongboth
groups
with
similarrecovery
timeand
speed.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Ketam
ine=35.4±6.7
Placebo
=36.44±7.17
Studyendpoint
Ketam
ine=14.18±11.83
Placebo
=14.33±9.46
Second
ary:
NA
Arabzadeh
etal.,
2018
OralKetam
ine50
mg/day
Allpatientsreceived
25-150
mg/daysertralin
e
Oral50
mg/dayplacebo
Allpatientsreceived
25-150
mg/daysertralin
e
Primary:
Changein
HDRSscores=−3
.41(−5.07
to−1
.75)
Second
aryou
tcom
emeasures:
1)At4weeks:−2
.61(−4.11
to−1
.11)
andat
6weeks:
−1.91(−3.34
to−0
.48)
2)Ketam
ine(85.4%
)vs
Placebo(42.5%
).3)
Ketam
ine(85.4%
)vs
Placebo(57.5%
)4)
Ketam
ine(22.0%
)vs
Placebo(15.0%
)
-Significantdifference
betweenKetam
ineand
placebogroupwas
observed
atweek2,
4,and6.
-Early
improvem
entandresponse
ratewas
greaterin
Ketam
ine(85.4%
,85.4%
)comparedto
theplacebogroup(42.5%
,57.5%),respectiv
ely.
-The
remission
ratesweresimilaram
ongboth
groups.
Burgeretal.,2016
IVKetam
ine0.2mg/kg
over
2min
IVNormalsalineinfusedover
2min
Primary:
2/3participantsreported
improvem
entin
suicidalideations
within
40min
insuicidality
whileno
improvem
entwas
reported
inplacebogroup.
Second
ary:
NA
Twoof
threewho
received
ketaminereported
improvem
entinsuicidality
andhopelessness
comparedto
none
amongthecontrolg
roup.
Canusoetal.,
2018
Intranasal84
mg
Esketam
ine.
Intranasal84
mgPlacebo.
Primary:
1)Changein
MADRS:
Esketam
inegroup=−1
3.4SD
=9.03)
Placebogroup=−9
.1(SD=8.38)
2)Esketam
ineVSPlacebo:
21.2%
and
9.7%
,respectively
Second
ary:
1)MADRSat24
h:leastsquare
mean
difference
=27.2,S
E=2.85,atday25:
least-square
meandifference
=24.5,S
E=
3.14.
-The
MADRSscores
improved
four
hours
afterthefirstdose
inboth
groups,w
itha
greaterim
provem
entin
Esketam
inegroup.
-A
greaterim
provem
entwas
reported
among
Esketam
inegroupcomparedto
placebo
groupatallstud
timepoint
during
blinded
phase.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
2)At24
hafterthe
firstdose:40.0%
and6.5%
,respectively,
andatday25:69%
and61%
respectively
Carspeckenetal.,
2018
IVracemicKetam
ine
1–2mg/kg
IVMethohexital1to
2mg/kg
Primary:
HAM-D
:Ketam
ine(F1,45
=7.8,MSE
=333.6,
P=0.008,
ηp2=0.16)vs
Methohexital
(F1,45
=0.43,m
eansquare
error
[MSE
]=18.4,P
=0.51,η
p2=0.01)
PHQ-9:K
etam
ine(F1,47
=6.45,M
SE=140.4,
P=0.01,η
p2=0.13)vs
Methohexital
(F1,47
=0.96,M
SE=21,P
=0.331,
ηp2=0.02)
PHQ-9
Baselinescores:
Ketam
ine=21.1
(±3.9)
Methohexital=
21.5
(±3.6)
StudyEndpoint:
Ketam
ine=7.2(±4.4)
Methohexital=
8.7(±5.3)
HAM-D
Baselinescores:
Ketam
ine=27.6
(±8.7)
Methohexital=
28.8
(±5.2)
StudyEndpoint:
Ketam
ine=12.3
(±7.6)
Methohexital=
15(±6.9)
Second
ary:
MOCA
Baselinescores:
Ketam
ine=27.4
(±2.0)
Methohexital=
26.7
(±3.9)
StudyEndpoint:
Ketam
ine=25.6
(±3.8)
-Patientsinbothgroups
reported
improvem
ent
aftertheECTcourse.
-PlasmaBDNFincreasedafterECTonly
intheketaminegroup
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Methohexital=
24.4(±4.1)
Chenetal.,2017
IVKetam
ine,0.3mg/kg.
Allpatient
received
ECT
treatm
ent.
IVNormalSalin
e0.3mg/kg.
Allpatient
received
ECT
treatm
ent.
Primary:
The
occurrence
globalcognitive
impairmentin
thecontrolgroupwas
higher
than
itwas
inthestudygroup.
The
declinein
theWechslerMem
ory
Scale-Chinese-Revisionscalewas
greaterin
thecontrolgroupthan
inthestudygroup.
Second
ary:
The
overallrem
ission
ratesinthecontrolgroup
andthestudygroupwere68%
and74%
respectiv
elywith
nosignificantdifference
amongboth
groups.
-The
overallremission
rateswere74%
and
68%
fortheKetam
ineandcontrolgroup
respectiv
ely.
-There
was
nostatistically
significant
difference
amongboth
groups.
-The
medianECTtim
eswere8forketamine
and9forthecontrolgroup.
-The
totalnumberof
ECTprocedures
were
511forKetam
ineand584forcontrolgroup.
Fanetal.,2017
IV0.5mg/kg
racemic
ketaminehydrochloride
over
40min
IV0.05
mg/kg
midazolam
over
40min
Primary:
BSI
Scores
Baselinescores:
Ketam
ine=17.06(SD=1.819)
Midazolam
=16.6
(SD=2.137)
Atday3:
Ketam
ine:1.69
(SD=1.93)
Midazolam
:3.42
(SD=1.75)
MADRS-SI
Baselinescores:
Ketam
ine=3.65
(SD=1.173)
Midazolam
=3.65
(SD=1.268)
Atday3:
Ketam
ine=1.77
(SD=1.84)
Midazolam
=3.52
(SD=1.89)
Second
ary:
MADRSScores
Baselinescores:
Ketam
ine=34.89(SD=8.04)
Midazolam
=34.19(SD=10.83)
-The
improvem
enton
MADRSscorewas
noticed
onday1andcontinuedon
day3,
butitwas
notobservableday7following
treatm
ent.
-There
was
also
improvem
entin
suicidal
ideatio
nson
BSI
andMADRS-SI.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Atday3:
Ketam
ine:25.09(SD=7.07)
Midazolam
:32.03(SD=7.21)
At7days:difference
was
insignificant.
Gam
bleetal.,
2018
IVKetam
ine,0.75
mg/kg
andremifentanil1
mcg/kg
Allpatientsreceived
8ECT
sessions
IVPropofol
1mg/kg
and
remifentanil1mcg/kg
Allpatientsreceived
8ECT
sessions
Primary:
Allpatientsin
theketaminearm
achieved
a50%
MADRSreductioncomparedwith
10(83%
)in
thePropofol
arm.
Medianinterquartile
range[IQR]numberof
ECTtreatm
entsto
achievea50%
MADRS
reductionis2[1–4]forKetam
ineand4
[2–7]forpropofol
group.
Second
ary:
-Allpatientsin
theketaminegroupachieved
remission
comparedwith
7in
thepropofol
group3ECTtreatm
entscomparedwith
7treatm
entsforpropofol.
-Patientsintheketaminegroupweremorethan
twiceas
likelyto
achieveresponse
onMADRS[H
R]:3.20,9
5%confidence
interval[(CI)]:2.00
to5.13
andalso
were
also
twiceas
likelyto
achieveremission
(HR:3
.67,95%
CI:2.13
to6.32)compared
with
thepropofol
arm.
-A
comparablechange
inALSscores
were
reported
amongboth
groups.
-MeanCADSSscores
werecomparableam
ong
both
groups.
-Tim
efrom
anesthesiatodischargewas
similar
betweengroups,6
3.5(18.2)
vs63.3
(15.8)
minutes
intheketaminearm
andpropofol
arm,respectively.
-About
100%
patientsin
Ketam
inegroup
achieved
50%
reductionin
MADRS
comparedto
placebo.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Ghasemietal.,
2013
IVKetam
ine,0.5mg/kg
over
45min,3
infusions
for45
min
over
3days
ECTon
3testdays
(every
48h)
Primary:
BDIScores
Baselinescores:
Ketam
ine=34.66(SD=10.7)
ECT=42.44(SD=9.53)
After
one-weekposttreatm
ent
Ketam
ine:10.88(SD=7.49)
ECT:15.66(SD=7.51)
HDRSScores
Baselinescores:Ketam
ine=30.22(SD=5.78)
ECT=35.88(SD=6.47)
After
one-weekposttreatm
ent
Ketam
ine:9.55
(SD=4.98)
ECT:14
(SD=4.9)
Second
ary:
NA
-There
was
asignificantim
provem
entin
patient
receivingKetam
inecomparedto
placebogroupwith
in24
hof
firstinfusion.
-Thisim
provem
entwas
observed
throughout
thestudyaftersecond
treatm
entand72
hpost-treatment.
-The
effectsize
weremoderateto
large
throughout
thestudy.
Haileetal.,2013
IVKetam
ine,0.5mg/kg,
Singledose
for40
min
for7days
Midazolam
0.045mg/kg
Primary:
Sevenpatientsreceivingketaminemet
response
criteriaatday7,
whereas
two
patientsreceivingmidazolam
metresponse
criteria.
Second
ary:
NA
-Participantstaking
Ketam
inereported
anincreasedin
plasmaBDNFlevelscompared
tonon-responsders.
-There
was
highly
significantnegative
correlationbetweenMADRSandBDNF
levelswith
ketamine(240
min
post
infusion).
-BDNFcanbe
used
asperipheralbiom
arker
forketamineantidepressantresponse.
Huetal.,2015
IVKetam
ine,0.5mg/kg
Oral Escitalopram
=10
mg/-
day
IVNormalsalin
e(placebo)
OralEscitalopram
=10
mg/day
Primary:
Cha
ngein
MADRSscores
Baselinescores:
Ketam
ine=32.3
(SD=6.5)
Placebo
=36.5
(SD=7.8)
After
four
weeks:
Ketam
ine:14.0
(SD=10.2)
Placebo:18.1
(SD=8.2)
Second
ary:
-Responseratewas
92.3%
and57.1%
for
Ketam
ine+Escitalopram
andplacebo+
Ketam
inegroup,
respectiv
ely.
-Fo
rTRD,the
response
ratewas
88.9%
and
33.3%
forKetam
ine+Escitalopram
and
placebo+Ketam
inegroup,
respectively.
-The
remission
ratewas
76.9%
and14.3%
for
Ketam
ine+Escitalopram
andplacebo+
Ketam
inegroup,
respectiv
ely.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Respo
nse:
At4weeks:
Ketam
inevs
Placebo:
92.3%
vs57.1%
Rem
ission
:At4weeks:
Ketam
inevs
Placebo:
76.9%
vs14.3%
QID
S-SR
Baselinescores:
Ketam
ine=16.5
(SD=5.3)
Placebo
=17.5
(SD=4.2)
After
four
weeks:
Ketam
ine:7.8(SD=5.8)
Placebo:10.0
(SD=4.6)
QID
S-Su
icide
Baselinescores:
Ketam
ine=1.9(SD=0.7)
Placebo
=1.4(SD=0.6)
After
four
weeks:
Ketam
ine:0.4(SD=0.9)
Placebo:0.2(SD=0.4)
-PatientsreceivingKetam
ineobserved
quicker
improvem
entthan
placebo.
Jafariniaetal.,
2016
OralKetam
ine50
mgthree
times
daily
Diclofenac50
mgthreetim
esdaily
Primary:
HDRSMeandifference:ketamine−diclofenac
atweek3:
1.85
(−0.48
to4.18)andatweek
6:(95%
CI):2.85
(0.54to
5.16)
HADSMeandifference
for
ketamine-dicolfenac
atweek3:
ketamine−-
diclofenac
(95%
CI):1.05
(0.45to
1.64),
andweek6:(95%
CI):0.75
(0.18to
1.32)
Second
ary:
MeanVASscorebetweenketamineand
diclofenac
atweek3:
2.05
(−8.27
to12.37)
andweek6:(95%
CI):−2
.90(−18.07to
12.27)
-A
significantdecrease
inHDRSscores
was
observerdwith
ketaminecomparedto
placebo.
-How
ever,b
othgroups
werecomparableat
week3.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
JarventaustaK.
etal.2
013
IVKetam
ine,0.4mg/kg
IVNormalsaline&
Propofol.
Primary:
Changein
MADRSscore:
S-ketamine=−2
6.9±
9.5
Normalsalin
e&
propofol=−2
7.1±
7.9
Second
ary:
NA
-There
was
acomparablereductionin
MADRSscores
amongboth
groups.
-The
was
nodifference
inspeedof
response
andnumberof
ECTsessions.
JiangM.,etal.,
2016
0.5mg/kg
(0.05ml/k
g)ketaminewas
givenatinductionof
anesthesia,followed
by0.25
mg/kg/h
(0.025
ml/k
g/h)
continuous
infusion
for
30min.
0.05
ml/k
gKetam
inewas
used
atinductionof
anesthesia,
follo
wed
by0.025ml/k
g/h
continuous
infusion
ofsalin
efor30
min.
Primary:
Differencein
PHQ-9
scores
forKetam
ine
grouppreoperativelyto
postoperatively
(days1and5):(t-value
=−2
.144,
F=−1
4.67,P
<0.01)
PHQ
scores
Preoperatio
nControl=3.63
±0.14
Ketam
ine=4.02
±0.13
Postoperativeday5
Control=2.92
±0.63
Ketam
ine=2.28
±0.61
Second
ary:
NA
-Therewas
asignificantd
ecreasein
PHQ-9
ofKetam
inegroupcomparedto
placeboat
postoperativeday1and5.
-BDNFlevelswerehigher
inKetam
inegroup
aftersurgery.
Tayyebi
etal.,
2018
IVKetam
ineBolus
and
infusions,
0.5–0.75
mg/kg
NA
Primary:
According
toHam
ilton
andBeckscore,the
treatm
entresponse
ininvestigated
patients
was
64%
and60%,respectively.
About
48%
participantson
HDRSand44%
onBDIrespondedto
treatm
enton
injection
0.5mg/kg
comparedto
80%
onHDRSand
76%
onBDIon
injection0.75
mg/kg/
Second
ary:
NA
-About
64%
and60%
patientsreported
improvem
enton
HDRSandBDI,
respectiv
ely.
-Fo
rdose
of0.5mg/kg
ofKetam
ine,48%
and
44%
reported
response
onHDRSandBDI,
respectiv
ely.
-Fo
rdose
of0.5mg/kg
ofKetam
ine,80%
and
76%
reported
response
onHDRSandBDI,
respectiv
ely.
-The
positiveresponse
was
highestduringfirst
twodays
andatweek1.
LaiR.etal.,
2014
IVKetam
ine,
0.1–0.4mg/kg
IVNormalSalin
ePrimary:
BaselineMADRSscore,29,2
7,29,2
8Three
offour
subjectsachieved
antidepressant
response
(50%
decrease
inMADRSscores)
-Fo
rtwopatients,response
was
noticed
at0.1mg/kg.
-Fo
rothertwo,
response
was
observed
atthe
highestdoses.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Second
ary:
NA
-Allpatientsrelapsed
within
aweek.
Lapidus
etal.,
2014
IntranasalKetam
ine,
50mg/day
IntranasalNormalsalin
ePrimary:
Estim
ated
meandifference
inMARDSscore
betweenketamineandplacebowas
7.6
(95%
CI:3.9–11.3)
Second
ary:
NA
-At24
h,therewas
significantim
provem
ent
amongKetam
ine(44%
)comparedto
placebo(6%).
-Ketam
inewas
associated
at40
min,4
and
48h.
-Nodifference
was
observed
at72
hor
7days.
Lenze
etal.,2016
IVKetam
ine,0.5mg/kg
NA
Primary:
BaselinescoreforMADRS
Saline&
40-m
ininfusion
group=34.0
(3.8)
96-hinfusion
group=31.9
(5.9)
50%
reductionin
MADRS:
4/10
inthe96-h
groupand2/10
inthe40-m
ingroupwererespondersatweek2;
ofthese,
2/10
inthe96-h
groupand1/10
inthe
40-m
ingroupmaintainedresponse
outto
week8.
Second
ary:
NA
-Bothgroups
reported
asignificantreduction
indepressive
symptom
scomparedto
baseline.
-HigherKetam
ineconcentrationwas
associated
with
abetterantid
epressant
response.
Loetal.,2016
Ketam
ine=0.1mg/kg,
increasing
by0.1mg/kg
upto
0.5mg/kg.
Ketam
inewas
giveninthree
routes
includingIV
,IM,
SC.
Midazolam
0.01
mg/kg
Primary:
12/15participantsmetthecriteriaforboth
response
andremission
atleastatonetim
epointduring
thetrial(acrossalldose
levels
andtim
epoints).
The
overallacuteresponse/rem
ission
rates
were75%
forIV
,60%
forIM
,and
100%
for
SCgroups.
Second
ary:
There
was
noevidence
oftreatm
entem
ergent
maniaatanyof
studytim
epoint,across
routes
ofadministrationanddoses.
There
was
noclinically
significantchange
inBPR
Sor
CADSS
was
observed
inthe
-12/15participantsachieved
response
and
remission
atleastatonetim
epointduring
thetrial.
-The
response
andremission
rateswere75%
(IV),60%
(IM)and100%
(SC).
-Dose-dependentresponse
butalso
ledto
increasedside
effects.
-The
meantim
eto
relapsewas
23.2
days
for
allroutine,9days
forIV
group,
11.7
days
forIM
group,
and34.5
days
forSC
group.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
midazolam
comparedto
differentroutes
ofketamine.
Murroughetal.,
2016
SingleIV
infusion
ofKetam
ineHydrochloride
0.5mg/kg
SingleIV
infusion
ofMidazolam
0.045mg/kg
Primary:
Cha
ngein
MADRSscores
Baselinescores:
Ketam
ine=32.6
(SD=6.1)
Placebo
=31.1
(SD=5.6)
After
24h:
Ketam
ine=14.77,
95%
CI(11.73–17.80)
Placebo=22.72,
95%
CI(18.85–26.59)
Second
ary:
-MADRSResponserate=Ketam
ine64%
VS
Placebo28%
-CGI-I=Ketam
ine62%
VSPlacebo24%
-CGI-S=
Ketam
ine53%
VSPlacebo8%
QID
Sscale
Baselinescores:
Ketam
ine=16.6
(SD=4.1)
Placebo
=16.3
(SD=4.5)
After
24h:
Ketam
ine=8.38,9
5%CI(6.71–10.05)
Placebo
=11.78,
95%
CI(9.63–13.92)
-The
response
rateswere64%
forKetam
ine
and28%
forplacebo,
respectivelyat24
hwith
numberneed
totreatof
2.4.
-There
was
asm
allworsening
ofsymptom
sover
timebutdepression
scores
werelower
forKetam
inegroup.
Fava
etal.,2018
IVKetam
ine0.1mg/kg,
0.2mg/kg,0
.5mg/kand
1.0mg/kg.
IVMidazolam
0.045mg.
Primary:
Pairw
isecompa
risons
ofallketaminegrou
pto
midazolam
onHAM-D
-6at
day3
−1.87,
95%
CI(−4.14,0
.41)
Pairw
isecompa
risons
ofeach
ketamine
grou
pto
midazolam
onHAM-D
-6at
day
30.1mg/kg
=−2
.04,
95%
CI(−5.04,0
.95)
0.2mg/kg
=−0
.36,
95%
CI(−3.18,2
.46)
0.5mg/kg
=−3
.21,
95%
CI(−5.97,−
0.44)
1.0mg/kg
=−1
.84,
95%
CI(−4.65,−
0.96)
-IV
Ketam
inewas
superior
toactiv
eplacebo
within
72hof
treatm
ent.
-The
dose
of0.5mgand1.0mg/kg
was
superior
toplaceboandlower
dosesof
ketamine.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Second
ary:
Statisticalsignificance
ofthegroup*tim
einteractioneffectwas
significantfor
onlyfor
theSD
Q(p=0.0105)andthePA
S(p=0.0341)in
the5-groupcomparison,
and
thePA
S(p=0.0332)andtheCGI-S
(p=0.0204)in
the2-groupcomparison.
Fernieetal.,2017
IVKetam
ineup
to2mg/kg
Allparticipantsreceived
ECT.
IVPropofol
upto
2.5mg/kg
Allparticipantsreceived
ECT.
Primary:
Cha
ngein
HDRSscores
Baselineseverity
Ketam
ine=27.19(6.47)
Propofol=24.79(8.50)
After
onemonth
post-ECT
Ketam
ine=14.08(8.08)
Propofol=12.08(9.86)
Cha
ngein
MADRSscores
Baselineseverity
Ketam
ine=36.38(8.29)
Propofol=35.68(8.39)
After
onemonth
post-ECT
Ketam
ine=17.85(13.15)
Propofol=17.15(13.75)
Second
ary:
CANTABSR
MBaselineseverity
Ketam
ine=0.71
(0.11)
Propofol=0.72
(0.15)
After
onemonth
post-ECT
Ketam
ine=0.70
(0.11)
Propofol=0.65
(0.12)
ketamineas
ananaesthetic
agentforECTwas
notassociated
with
acceleratio
nof
the
antidepressanteffectof
ECT
Dalyetal.,2017
IntranasalEsketam
ine
28mg,
56mg,
84mg.
Intranasalplacebo
Primary:
Meandifference
from
placebo
Esketam
ine28
mg:
−4.2
(2.09)
-There
was
dose-dependent
statistically
sig-
nificant
treatm
entam
ongalltreatm
ent
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Esketam
ine56
mg:
−6.3
(2.07
Esketam
ine84
mg:
−9.0
(2.13)
Second
ary:
Baselineandlastday
groups
comparedto
placeboafteraweekof
treatm
ent.
-Durationof
effectivenesswith
28mgdose
was
shorter.
Grunebaum
etal.,
2018
IVKetam
ine0.5mg/kg
IVmidazolam
0.02
mg/kg
in100mlnorm
alsaline
Primary:
Average
SSIscoreatday1:
DifferencebetweenKetam
ineto
Midazolam
=4.96
(95%
CI2.33
to7.59)
Second
ary:
-The
proportionof
responderson
SSIw
as55%
afterketaminecomparedto
Midazolam
atday1.
-PO
MSScaleim
provem
entafterketamine
comparedwith
midazolam
=(Estim
ate=21.19(95%
CI=
2.95
to39.43).
-Depression=Estim
ate=7.65
(95%
CI=
1.36
to13.94)
-Changein
HDRS-17
=Estim
ate=2.83
points
(95%
CI=
−0.12to
5.77).
-Changein
HDRS-24
=3.54
points(95%
CI=
−0.29to
7.36)
Self-rated
BDI=
4.66
points(95%
CI=
−0.04
to9.36).
AsingleKetam
ineinfusion
resultedin
agreaterreductionin
suicidalideatio
nsatday
1comparedtoactiv
eplacebo.The
Ketam
ine
groups
show
edagreaterim
provem
entfor
depression
comparedto
activeplacebo.
Kudoh
etal.,2002
Group
A:S
ingleIV
infusion
of1.0mg/kg
ofKetam
ine,1.5mg/kg
ofPropofol,and
2μg/kg
ofFentanyl
Group
B:SingleIV
infusion
of1.5mg/kg
ofPropofol
and2
μg/kg
ofFentanyl
Primary:
Cha
ngein
HDRSscores
Baselinescores:
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
ketaminenotonly
improved
the
depressive
symptom
spostoperativelybut
also
reducedpain
indepressedpatientswho
underw
entorthopedicSu
rgery.
Depressed
mood,
suicidaltendencies,som
aticanxiety,
andhypochondriasissignificantly
decreased
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Group
C=4.8±1.6
Second
ary:
Postoperativepain
scores
inGroup
Aat8and
16haftertheanestheticeffectwere
significantly
lower
than
thosein
Group
B.
There
wereno
significantdifferencesin
the
otherpostoperativepain
scores
betweentwo
groups
for4days
aftersurgery.
PPo
stoperativepain
scores
forGroup
Cat8,16,
24,48,and72
hwere20.2□8.4,18.4□7.5,
11.9
□6.1,
8.7□5.5,
and5.2□3.2,
respectiv
elyaftertheendof
anesthesia.
Salehi
etal.,2015
IVKetam
ine0.8mg/kg
Participantsreceived
atotal
ofeightECTsessions.
IVSo
dium
thiopental
1mg/kg-1.5
mg/kg
Participantsreceived
atotalof
eightECTsessions.
Primary:
Cha
ngein
HMDRSscores
Baselinescores:
Ketam
ine=29.82±7.3
Sodium
thiopental=28.86±7.6
After
session#8:
Ketam
ine=8.32
±5.17
Sodium
thiopental=10.53±7.87
Second
ary:
Systolicanddiastolic
bloodpressure
have
statistically
significantdifference
between
ketamineandsodium
thiopentalin
all
sessions.
The
depression
scores
improved
aftereach
ECTsessionbutim
provem
entwas
faster
inKetam
inegroup.
Singhetal.,2016
Intravenous
Ketam
ine(0.5
mg/kg)two
orthreetim
esweekly
Intravenous
placebo(0.9%
Sodium
chloride
forinjection)
twoor
three
times
weekly
Primary:
Cha
ngein
MADRSscore
Ketam
inetwicedaily
:218.4(SD=12.0)
Placebo
=25.7
(SD=10.2)
Ketam
inethreetim
esdaily
=217.7(SD=7.3)
Placebo
=23.1
(SD=5.7)
Second
ary:
Ketam
inewas
effectiveatboth
frequenciesfor
depression
comparedto
placebo.
The
meandifference
inMADRSscores
was
comparableam
ongboth
groups.
Onsetof
antid
epressantw
asnoticed
with
infirst
weekandwas
maintainedthroughday15
forboth
Ketam
inegroupcomparedto
placebo.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
The
totalchan
gein
MADRSscorefrom
baselin
eto
day29
forbo
thketamine
grou
psKetam
inetwiceadaily
=221.2(SD=12.9)
Placebo
=24.0
(SD=9.1)
Ketam
inethreetim
esdaily
=221.1(SD=11.2)
Placebo
=23.6
(SD=6.6)
MADRSrespon
seat
day15
Ketam
inetwiceadaily
vsplacebo=68.8%
vs15.4%
Ketam
inethreetim
esadaily
vsplacebo=6.3%
vs53.8%
MADRSremission
atda
y15
Ketam
inetwiceadaily
vsplacebo=7.7%
vs37.5%
Ketam
inethreetim
esadaily
vsplacebo=0%
vs23.1%
MADRSon
setof
respon
sein
week1
Ketam
inetwiceadaily
vsplacebo=6.3%
vs38.9%
Ketam
inethreetim
esadaily
vsplacebo=0%
vs4%
Duringthe2-weekopen-labelketaminephase,
themeanCGI-SandPG
I-Sscores
were
similarin
both
groups
The
treatm
entresponse
was
similaram
ong
both
groups
during
open-labelphase.
Singhetal.,2016
SingleIV
Esketam
ine
0.20
mg/kg,o
rsingleIV
Esketam
ine0.40
mg/kg
over
40mins
SingleIV
infusion
ofplacebo
(.9%
salin
esolutio
n)Over
40mins
Primary:
Cha
ngein
MADRSscore
compa
redto
placebo
Placebo
=23.8
(SD=2.97)
Esketam
ine.20mg/kg
=216.8(SD=3.00)
Esketam
ine.40mg/kg
=216.9(SD=2.61)
Second
ary:
The
totalchan
gein
MADRSscorefrom
baselin
eto
day3
-The
depression
scores
improved
forboth
groups
taking
Esketam
inegroups
compared
toplacebo.
-The
proportio
nof
responderswere67%
and
64%
forboth
Esketam
inegroups.T
here
wereno
respondersam
ongplacebogroup.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Placebo=−2
.3(SD=3.38)
Esketam
ine.20mg/kg
=−1
6.3(SD=3.45)
Esketam
ine.40mg/kg
=−1
3.4(SD=3.03)
Respo
ndersto
firstdo
seEsketam
ine0.2mg/kg
=67%
Esketam
ine0.4mg/kg
=64%
Placebo=0%
Cha
ngein
CGI-Sscore
Placebo=−0
.2(SD=0.63)
Esketam
ine.20mg/kg
=−1
.3(SD=1.5)
Esketam
ine.40mg/kg
=−1
.4(SD=1.36)
Cha
ngein
PGI-SscorePlacebo
=−0
.3(SD=0.48)
Esketam
ine.20mg/kg
=−0
.8(SD=0.97)
Esketam
ine.40mg/kg
=−.6(SD=0.82)
Sosetal.,2013
SingleIV
loadingdose
of0.27
mg/kg
followed
bymaintenance
dose
of0.27
mg/kg
SingleIV
infusion
ofplacebo
(.9%
salin
esolutio
n)Primary:
Cha
ngein
MADRStotalscore
Day
1=5.7(95%
CI3.4–7.9)
Day
4=4.7(95%
CI2.5–7.0)
Day
7=4.0(95%
CI1.8–6.2
Second
ary:
Respo
nseratesat
day7
Ketam
ine=40.7%
Placebo=11.1%
Ketam
ineserum
levelsAfter
10min=306±136ng/m
lAfter
30min
=237±95
ng/m
lKetam
inemetab
olitelevels
After
10min=11
±7ng/m
lAfter
30min=50
±21
ng/m
..There
wereno
differencesfoundbetween
respondersandnon-respondersin
ketamine
and/or
nor-ketamineserum
levels.
Therewas
areductionin
thecoresymptom
sof
depression
inthefollowingweekwith
maxim
umon
dayseven.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Suetal.,2017
IVKetam
ine=0.2mg/kg,
0.5mg/kg.
SingleIV
infusion
ofplacebo
(salinesolution)
Primary:
HAM-D
Scores
Baselineseverity
(Estim
ated
LeastSq
uare
Means):
Placebo=1.32
Ketam
ine0.2mg/kg
=1.32
Ketam
ine0.5mg/kg
=1.32
At28
days
(Estim
ated
LeastSq
uare
Means):
Placebo=1.11
Ketam
ine0.2mg/kg
=0.91
Ketam
ine0.5mg/kg
=0.96
Second
ary:
Respo
nserates
Ketam
ine0.5mg/kg
=45.8%
Ketam
ine0.2mg/kg
=39.1%
Placebo=12.5%
Respo
nseRateby
BDNFVal66Met
Genotyp
eVal/Val=17%
Val/M
et=56.3%
Met/M
et=26.8%
There
was
nodifferencesbetweencarriersof
theMetalleleandVal/Valpatients(re-
sponderrate:33.9%
vs25.0%).
BDNFgenotype
isnota
significantpredictor
oftheoutcom
e.
The
dose
of0.5mg/kg
was
moreeffective
comparedto
0.2mg/kg
andplacebo.
There
was
nosignificantdifference
between
carriersof
theMetalleleandVal/Valpa-
tientsin
efficacy
forKetam
ine
Wangetal.,2012
SingleIV
dose
of0.8mg/kg,K
etam
ineor
SingleIV
dose
of0.8mg/kg
Ketam
ineplus
1.5mg/kg
Propofol
Allparticipantsreceived
ECT.
SingleIV
dose
of1.5mg/kg
Propofol
Allparticipantsreceived
ECT.
Primary:
Cha
ngein
HDRSscores
Baselineseverity
Ketam
ine&
propofol=28.00±4.88
Ketam
ine=27.00±3.93
Propofol=28.16±2.48
After
7days
Ketam
ine&
propofol=6.94
±1.57
Ketam
ine=6.75
±0.96
The
HDRSscores
improved
quicklyin
ketaminegroupandKetam
ineandPropofol
groupcomparedto
Propofol
only
group.
The
improvem
entin
depression
scores
were
significantly
greaterin
ketaminegroupand
Ketam
ineandPropofol
groupcomparedto
Propofol
only
group.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
Propofol=11.08±2.78
Second
ary:
NA
Xuetal.,2017
IVKetam
ine0.5mg/kg.
Isofibrillarsalin
ePrimary:
Cha
ngein
HAMD
scores
Baselineseverity
Ketam
ine=18.82±2.82
Control
group=18.55±3.21
After
7days
Ketam
ine=17.36±6.25
Control
group=13.45±5.21
Second
ary:
NA
The
HAMDSscores
improved
atday1,
3and
7comparedto
placebo.
How
ever,thischange
was
notstatistically
significant.
Xuetal.,2017
SingleIV
dose
of0.25
mg/kg
Ketam
ine
SingleIV
infusion
ofplacebo
(.9%
salin
esolutio
n)Primary:
EDRSscores
3da
yspo
stpa
rtum
Ketam
ine=7.2±3.9
Saline=7.2±4.2
EDRSscores
6-weeks
postpa
rtum
Ketam
ine=5.6±3.9
Saline=5.7±4.3
Occurrenceof
postpa
rtum
depression
Ketam
ine=16%
Saline=17.8%
Second
ary:
NRSscores
3da
yspo
stpa
rtum
Ketam
ine=4
(0–7)
Salin
e=4(0–8)
NRSscores
6-weeks
postpa
rtum
Ketam
ine=1(0–8)
Salin
e=2(0–9)
Nosignificantdifferenceswerefoundin
the
prevalence
ofpostpartum
depression
Yoosefietal.,
2014
IVinfusion
ofketamine
1mg/kg
or2mg/kg,
IVinfusion
ofthiopental
2mg/kg
or3mg/kg,
Primary:
Cha
ngein
HAMD
scores
Baselineseverity
-There
was
significantin
depression
scores
amongKetam
inegroupbefore
second
ECT
sessioncomparedto
Thiopental.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
ECTsessions
werecarried
out3tim
esaweekfora
totalof
6sessions
over
3weeks
ECTsessions
werecarriedout3
times
aweekforatotalof
6sessions
over
3weeks
Ketam
ine=23.60
Thiopental=
22.86
After
4days
Ketam
ine=17.07
Thiopental=
17.29
Second
ary:
Cha
ngein
MMSE
scores
Baselineseverity
Ketam
ine=25.60
Thiopental=
24.79
After
4days
Ketam
ine=27.87
Thiopental=
25.29
Seizurepa
rameters
Ketam
ineseizureduratio
n=27.47to
31.87s
Ketam
ineelectricaldose=28.67to
36Thiopentalseizureduratio
n=19.27to
25.57s
Thiopentalelectricaldose=36.43to
62.86
Inboth
groups,b
aselinevalues
ofheartand
MeanArterialPressure
werenotshow
nto
besignificantly
different.
-Atthe
endof
study,both
groups
observed
anim
provem
entin
depression
scores.
Zarateetal.,2006
SingleIV
dose
of0.5mg/kg
Ketam
inein
twophases
SingleIV
infusion
ofplacebo
(salinesolution)
Primary:
Cha
ngein
HDRSscores
Ketam
ine=−5
6.2±20.4
Placebo=−9
.8±20.1
Second
ary:
BPRSpo
sitive
symptom
ssubscalescores
for
participan
tsreceivingKetam
ine
compa
redto
placebo
Drug,
F1,200
=4.23;P=.04;
time,
F8,200
=9.31;P□.001;
drug
□tim
e,F8
,200
=6.89;P□.001)
Ketam
inewas
effectivefordepression
comparedto
placebo.
Thisbenefitwas
maintainedforaweekaftertheKetam
ine
dose.
Psychiatric Quarterly
Table1
(contin
ued)
Study
Interventiongroup
Com
parisongroup
Meanchange
inprim
aryoutcom
emeasures
Summaryof
results.
YMRSscores
forpa
rticipan
tsreceiving
ketaminecompa
redto
placebo
Days1to2(drug,F1
,201
=3.08;P
=.08;tim
e,F8
,201
=3.54;P□.001;
drug
□tim
e,F8
,201
=4.68;P□.001
Respo
nserates
Ketam
ine=71%
Placebo=0%
Rem
ission
rates
Ketam
ine=35%
Placebo=0%
BHS,
BeckHopelessnessScale;BSI,BeckSu
icidality
Ideatio
n;ECT,
Electroconvulsive
Therapy;HAM-D
,Ham
ilton
DepressionRatingScale;
HRDS,
Ham
ilton
DepressionRating
Scale;ID
S-CR,Inventoryof
DepressiveSy
mptom
atology—
Clin
icianRated;MADRS,
Montgom
ery-ÅsbergDepressionRatingScale;
MADRS-SI,Montgom
ery-
AsbergDepression
RatingScale;
MDD,Major
DepressiveDisorder;
MoC
A,MontrealCognitiv
eAssessm
ent;PHQ-9,Patient
Health
Questionnaire;QID
S-SR
,Quick
Inventoryof
Depressive
Symptom
atology–Self-Report;SA
FTE
E,Sy
stem
atic
Assessm
entforTreatmentEmergent
Effects;TR
D,TreatmentResistant
Depression;
WMS-RC,WechslerMem
oryScale-
Chinese
Revision
Psychiatric Quarterly
Table2
Baselinecharacteristicsof
patientsin
theincluded
trials
Study
Groups
Duration
Sample
[n]
Age
[years]
[Mean/Median]
Singleinfusion
vsmultipleinfusion
Doserange(m
g)
Alizadeh
etal.,2015
Ketam
ine&
Propofol
NA
2234.27±10.66
Multip
le0.3mg/kg
Salin
e&
Propofol
2035.1±12.44
0.3mg/kg
Arabzadeh
etal.,2018
Ketam
ine
6weeks
4134.31±6.73
NA
(oraldosage)
50mg/day
Placebo
4033.72±8.34
50mg/day
Burgeretal.,2016
Ketam
ine
2weeks
328
Single
0.2mg/kg
Placebo
727
0.2mg/kg
Canusoetal.,2018
Esketam
ine
4weeks
3535.7±13.40
NA
(intranasal)
84mg
Placebo
3136.0±12.82
84mg
Carspeckenetal.,2018
Ketam
ine
Ketam
ine=46
weeks
Methohexital=
53weeks
2350
±12
Single
1–2mg/kg
Methohexital
2747
±12
1–2mg/kg
Chenetal.,2017
Ketam
ine
4weeks
6340.94±15.41
Multip
leinfusions
0.3mg/kg
Control
6437.44±14.16
0.3mg/kg
Fanetal.,2017
Ketam
ine
7days
2046.75±14.04
Single
0.5mg/kg
Midazolam
1744.65±15.1
0.5mg/kg
Fernieetal.,2017
Ketam
ine
One
month
2051.76±9.97
Multip
leinfusions
Upto
2mg/kg
Propofol
2049.88±12.53
Upto
2.5mg/kg
Gam
bleetal.,2018
Ketam
ine
4weeks
1242
±16
Singleinfusion
vsmultip
leinfusion
0.75
mg/kg
Propofol
1246.5±16
0.75
mg/kg
Ghasemietal.,2013
Ketam
ine
7days
935.22±13.63
Multip
leinfusions
0.5mg/kg
ECT
940
±16.41
0.5mg/kg
Haileetal.,2013
Ketam
ine
1week
1548.53±3.30
Single
0.5mg/kg
Midazolam
742.71±4.85
0.5mg/kg
Huetal.,2015
Ketam
ine
4weeks
1336.7±14
Singleinfusion
vsmultip
leinfusion
0.5mg/day
Placebo
1441
±11.1
0.5mg/day
Jafariniaetal.,2016
Ketam
ine
6weeks
2040.7±8.71
NA
150mg
Diclofenac
2038.95±9.22
150mg
Ja¨rventaustaK.etal.
2013
S-Ketam
ine
2weeks
1648.4
Multip
le0.4mg/kg
Propofol
&norm
alsalin
e16
53.7
0.4mg/kg
JiangM.,etal.,2016
Ketam
ine
5days
6043.38±0.95
NA
0.25–0.5
mg/kg
Control
6041.40±0.16
0.25–0.5
mg/kg
Psychiatric Quarterly
Table2
(contin
ued)
Study
Groups
Duration
Sample
[n]
Age
[years]
[Mean/Median]
Singleinfusion
vsmultipleinfusion
Doserange(m
g)
Tayyebi
etal.,2018
Bolus
Ketam
ine
2months
2540.84±11.75
Single
0.5mg/kg
(Bolus)
2542.84±12.17
0.75
mg/kg
(Bolus)
Infusion
Ketam
ine
2539
±11.49
0.5mg/kg
(Infusion)
2539.72±10.18
0.75
mg/kg
(Infusion)
LaiR.etal.,
2014
Ketam
ine
5weeks
4NA
Multip
le01–0.4
mg/kg
Normalsalin
eNA
Lapidus
etal.,2014
Ketam
ine
2weeks
1848.0±12.8
Single
IntranasalKetam
ine
50mg/day
Placebo
Intranasal0.9%
salin
e(Placebo)
Lenze
etal.,2016
96hinfusion
8weeks
1044.6±12.8
Single
0.6mg/kg/h
Salin
eforfirst95
hand20
min
follo
wed
by0.5mg/kg
Ketam
ine
forfinal40
min
1042.5±13.8
Saline,40-m
inKetam
ineat0.5
mg/kg
Loetal.,2016
Ketam
ine
7days
1148.5±11
Multip
leinfusions
0.1mg/kg
-0.5mg/kg
Midazolam
30.01
mg/kg
Murroughetal.,2016
Ketam
ine
7days
4746.9±12.8
Single
0.5mg/kg
Midazolam
2542.7±11.6
Single
0.045mg/kg
Fava
etal.,2018
Ketam
ine
30days
8043.1±11.9
45.5±14.6
48.6±12.9
47.4±10.1
Single
0.1mg/kg
0.2mg/kg
0.5mg/kg
1.0mg/kg
Midazolam
1945.6±13.8
–Dalyetal.,2017
Esketam
ine28,5
6,84
mg
130days
3444.7
[10.0]
Multip
ledoses
Esketam
ine28,5
6,84
mg
Placebo
33Placebo
Psychiatric Quarterly
Table2
(contin
ued)
Study
Groups
Duration
Sample
[n]
Age
[years]
[Mean/Median]
Singleinfusion
vsmultipleinfusion
Doserange(m
g)
Grunebaum
etal.,2018
Ketam
ine
One
day
4040.7±13.1
Singleinfusion
0.5mg/kg
Midazolam
4038.4±13.2
0.02
mg/kg
Kudoh
etal.,2002
Group
APropofol,
Fentanyl,K
etam
ine
1week
3546.9±8.8
Singleinfusion
1.0mg/kg
ofketamine,
1.5mg/kg
ofpropofol,
and2□g
/kgof
fentanyl
Group
BPropofol,
Fentanyl
3548.2±7.4
1.5mg/kg
ofpropofol
and2□g
/kgof
fentanyl
Group
CPropofol,
Fentanyl,K
etam
ine
2046.2±10.3
1.0mg/kg
ofketamine,
1.5mg/kg
ofpropofol,
and2□g
/kgof
fentanyl
Salehi
etal.,2015
Ketam
ine
8session
80Not
mentioned
Multip
leinfusions
0.8mg/kg
Sodium
thiopental
80Not
mentioned
1–1.5mg/kg
Singhetal.,2016
Ketam
ine
15days
35BID
=45.7±9.6
TID
=43.3±12.0
Multip
leinfusions
0.5mg/kg
twicedaily
VS0.5mg/kg
thrice
daily
Placebo
33BID
=40.3±11.8
TID
=46.1±10.5
Singhetal.,2016
Esketam
ine
4days
200.2mg/kg
=44.7±13.38
0.4mg/kg
=41.8±(11.63)
Multip
leinfusions
0.2,
0.4mg/kg
Placebo
1042.7±(10.89)
Sosetal.,2013
Ketam
ine
2weeks
1142.2±15.1
Multip
leinfusions
0.5mg/kg
Placebo
1944.6±10.9
Suetal.,2017
Ketam
ine
2weeks
470.2mg/kg
=45.0±12.3
0.5mg/kg
=48.5±11
Singleinfusion
0.2,
0.5mg/kg
Placebo
2448.6±8.2
Wangetal.,2012
Ketam
ine
One
week
1656.2±11.5
Singleinfusion
0.8mg/kg
Ketam
ine&
Propofol
1658.6±16.3
Propofol
1653.8±15.2
Xuetal.,2017
Ketam
ine
1week
5042.36±7.28
Singleinfusion
0.5mg/kg
Psychiatric Quarterly
Table2
(contin
ued)
Study
Groups
Duration
Sample
[n]
Age
[years]
[Mean/Median]
Singleinfusion
vsmultipleinfusion
Doserange(m
g)
Salin
e43.27±6.6
Xuetal.,2017
Ketam
ine
6weeks
165
31±4
Singleinfusion
0.25
mg/kg
Salin
e165
32±4
Yoosefietal.,2014
Ketam
ine
6ECTsessions
over
2weeks
with
3sessions
every
week
1640.87
Multip
leinfusions
1to
2mg/kg
Thiopental
1547
2to
3mg/kg
Zarateetal.,2006
Ketam
ine
One
week
946.7±11.2
Singleinfusion
one
weekapartin
cross-over
study
0.5mg/kg
Placebo
9
Study
Male
[%]
AdjunctMedications
(Mentio
nthepercentage
taking
medications
ifanyandwhatare
thosemedications)
Com
mon
side
effects
Siteof
trial
Alizadeh
etal.,2015
6(27%
)Patientswereprescribed
medications
butnames
werenotmentio
ned.
Noside
effectswerereported
Iran
7(35%
)Arabzadeh
etal.,2018
26(63.4%
)Sertralin
eAbdom
inalpain,n
ausea,trem
or,and
dissociation.
Com
parableside
effects
betweengroups.
Iran
24(60%
)
Burgeretal.,2016
2(67%
)Not
mentio
ned
Noside
effectswerereported.
USA
5(71%
)Canusoetal.,2018
13(37.4%
)Standard
antidepressantstartedatday1,titrated
during
2weeks
andcontinued.
Ifalready
onADT,contin
ued.
Nausea,dizziness,dysgeusia,dissociation,
headache,v
omiting,anxiety,p
aresthesia,
sedatio
n,somnolence,euphoricmood,
vertigo.
USA
10(32%
)
Carspeckenetal.,2018
17(74%
)Allpatientsreceived
ECTsessions.C
ontinued
useof
ADTs.
Not
reported.
USA
24(89%
)Chenetal.,2017
21(33.3%
)Allpatientsreceived
12ECTsession
(three
perweek)
Nodifference
inside
effectsam
ong
both
groups.
USA
23(35.9%
)Fanetal.,2017
8(40%
)NA
Not
reported.
China
4(23.5%
)Fernieetal.,2017
18(45%
)Norestrictions
wereplaced
onthepsychiatric
medications
andor
treatm
entsprescribed
Not
reported.
Scotland
Psychiatric Quarterly
Table2
(contin
ued)
Study
Male
[%]
AdjunctMedications
(Mentio
nthepercentage
taking
medications
ifanyandwhatare
thosemedications)
Com
mon
side
effects
Siteof
trial
either
before
orduring
thecourse
ofthetrial.
Allparticipated
received
ECT.
Gam
bleetal.,2018
6(50%
)Allpatientsreceived
8ECTsessions
Hypertension,
hypotension,
nausea,
vomiting
headache
Canada
6(50%
)Ghasemietal.,2013
4(44.4%
)Allpatientsreceived
ECTsessions.
Tem
porary
non-significantincrease
inpulseandsystolicbloodpressure.
Iran
444.4%)
Haileetal.,2013
Not
mentioned
Singledose
for40
min.
Not
reported.
USA
Not
mentio
ned
Huetal.,2015
6(46.2%
)Allpatientsreceived
escitalopram
10mg/day
Nightmares,restlessness,d
izziness,
nausea,h
eadacheandincreasing
salivation
China
4(28.6%
)Jafariniaetal.,2016
5(25%
)None
Transient
loss
ofappetite,blurredvision,
trem
or,abdom
inalpain
Iran
5(25%
)Ja¨rventaustaK.etal.2013
8(50%
)Antidepressant,antip
sychotic,antidepressants+
antip
sychotics,benzodiazepines
Bothgroups
received
ECTtreatm
ent.
Posttreatm
entdisorientatio
nand
restlessness.
USA
5(31.2%
)
JiangM.,etal.,2016
34(57%
)None
Side
effectswerecomparableam
ong
both
groups.
China
33(55%
)Tayyebi
etal.,2018
15(60%
)None
Side
effectswerenotreported.
Iran
14(56%
)11
(44%
)10
(40%
)LaiR.etal.,
2014
2(50%
)Alprazolam,o
lanzapine,quetiapine,tranylcypromine
Transient
tachycardia,andhypertension.
UK
Lapidus
etal.,2014
10(50%
)Nam
esof
dugs
notmentioned.
Smallincrease
inpsychosis,dislocation,
andsystolicbloodpressure.O
ther
side
effectswerefeelingstrange,poor
mem
ory,
andweaknessor
fatigue.
USA
Lenze
etal.,2016
2(20%
)Clonidine,S
SRI,SN
RIagents,aripiprazole
Mild
andtransientside
effectswere
reported
forbloodpressure.
USA
4(40%
)Loetal.,2016
4(26.6%
)Patientswereprescribed
psychotropic
medications
butnames
werenot
mentio
ned.
Mild
depersonalization,
derealization,
alteredbody
andtim
eperception.
Australia
Not
mentio
ned
Psychiatric Quarterly
Table2
(contin
ued)
Study
Male
[%]
AdjunctMedications
(Mentio
nthepercentage
taking
medications
ifanyandwhatare
thosemedications)
Com
mon
side
effects
Siteof
trial
Transient
increase
inpulse,systolic
anddiastolic
bloodpressure.
Fatigue,light-headedness,dizziness,
blurredvision,d
rymouth
andem
otional
liability
Murroughetal.,2016
21(45%
)Zolpidem
Dizziness,b
lurred
vision,h
eadache,nausea
orvomiting,dry
mouth,poorcoordination,
poor
concentration,
andrestlessness.
USA
14(56%
)
Fava
etal.,2018
42(52.5%
)Benzodiazepine
Non-benzodiazepine
hypnotics
SSRIs
SNRIs
TCAs
Bupropion
Mirtazapine
Vortio
xetin
e
Highsystolicanddiastolic
bloodpressure
amongparticipantsin
ketaminegroups.
USA
8(42.1%
)
Dalyetal.,2017
29(43.3%
)Participantscontinuedtheirexisting
antid
epressanttreatm
entduring
thestudy
Dizziness,h
eadache,anddissociativ
esymptom
sUSA
,Belgium
Grunebaum
etal.,2018
18(45%
)Antidepressants,anticonvulsants,
antipsychotics,benzodiazepines,lithium
(above
medications
werestoppedat
least24
hpre-infusion)
Four
patientswith
suicideattempts
(3afterand1before
studyprocedures),
and3inpatient
admissionsforsuicidal
ideations.
Transient
increase
inbloodpressure.
USA
14(35%
)
Kudoh
etal.,2002
Not
mentio
ned
Alldepressedpatientsweremedicated
byantidepressantsformorethan
ayear
Ventricular
ectopicrhythm
Japan
Salehi
etal.,2015
37(46.2%
)Not
mentioned
Increasedbloodpressure,h
eadache,nausea,
andfear
with
theillusionof
awakenings
Iran
37(46.2%
)Singhetal.,2016
11(31.4%
)Patientscontinuedanyantidepressantmedications
they
werereceivingatscreening,
atthesame
stabledosagesthroughout
thestudy.
The
antidepressantsmostcommonly
used
(>10%
ofpatientsin
each
treatm
entgroup)
atbaseline
Headache,anxiety,
dissociatio
n,nausea,
anddizziness
USA
11(31.4%
)
Psychiatric Quarterly
Table2
(contin
ued)
Study
Male
[%]
AdjunctMedications
(Mentio
nthepercentage
taking
medications
ifanyandwhatare
thosemedications)
Com
mon
side
effects
Siteof
trial
werefluoxetin
e,citalopram
,and
bupropion;
theseagentswerecontinuedthroughout
thestudy.
Singhetal.,2016
8(40%
)Not
mentioned
The
mostcommon
side
effectswerenausea
andheadache
forEsketam
ine0.2mg/kg
andheadache,d
issociation,
andnausea
forEsketam
ine0.40
mg/kg.
Belgium
,Germany,Po
land
4(40%
)
Sosetal.,2013
5(45.5%
)Dissociation,
perceptualdisturbances,
confusion,
mild
increasesin
blood
pressure,emotionalbluntingand
euphoria.
Czech
Republic
10(52.6%
)
Suetal.,2017
9(19.1%
)Not
mentioned
Increasedin
systolicbloodpressure
Taiwan
9(37.5%
)Wangetal.,2012
6(50%
)SS
RI,TCA,A
typicalantipsychotics,
Benzodiazepines
Hypertensionduring
theECTsession,
angialgiaatthesiteof
injectionof
theanestheticandsenseof
fear
upon
awakeningfrom
anesthesia
USA
7(58%
)5(42%
)
Xuetal.,2017
0Not
reported
Not
reported.
China
0Xuetal.,2017
0Single
Dizziness,d
rowsiness,d
iplopia,
hallu
cinations,h
eadache,and
vomiting
China
0
Yoosefietal.,2014
7(50%
)Not
mentioned
Increase
inBP10
min
afterinduction
amongKetam
inegroup
Iran
8(53.3%
)Zarateetal.,2006
0Participantsdidnotreceivethese
medications
during
thelength
ofstudy.
Perceptualdisturbances,confusion,
elevations
inbloodpressure,
euphoria,d
izziness,and
increasedlib
ido
USA
ADT,
antidepressanttreatm
ent,ECT-Electroconvulsive
therapy;
NA,Not
Applicable;SN
RI,SelectiveNorepinephrineRe-UptakeInhibitor;SSRI,SelectiveSerotoninRe-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]. Theinclusion criterion was TRD (n = 13) and moderate to severe MDD (n = 22). Ketamine wasalso used as anesthetic and antidepressant in participants who underwent orthopedic surgeryand unilateral mastectomy [27,28]. In one study, participants were newly diagnosed withbreast cancer [29]. Another study focused on prevention of depression in pregnant patientsundergoing elective cesarean section [26].
Scales for Outcome Measures
The primary outcome was measured using various rating scales. The breakdown of thesemeasure was: Hamilton Depression Rating Scale (HDRS) (n = 22), Montgomery–ÅsbergDepression Rating Scale (MADRS) (n = 18), Beck Depression Inventory (BDI) (n = 5), andPatient Health Questionnaire (PHQ) - 9 (n = 3).
Dose of Ketamine
In 32 studies, Ketamine was used in the treatment arm whereas three studies usedEsketamine as the active agent. It was administered as Intravenous (IV) infusion in 30studies, intranasal in two studies, and orally in three studies. One study administeredKetamine through a subcutaneous route. Intravenous Ketamine was used in varyingdosages ranging from 0.1 mg/kg to 1 mg/kg day in 29 studies. Three studies used a doserange of up to 2 mg/kg. Intranasal Ketamine was administered between dose ranges of 28to 84 mg. Dosage of oral Ketamine ranged from 50 mg/day to 50 mg three times a day.Studies comparing the dose-dependent response found a greater response at doses of0.5 mg/kg to 1 mg/kg IV Ketmaine [24,30,31] whereas Singh et al., 2016 found similarresponse 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 improvementcompared 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 groups[32]. However, the antidepressant benefits lasted up to 72 h on BDI scale and one weekon HDRS scale after the last infusion of Ketamine. Among studies with favorableresponses, two studies used Ketamine as an anesthetic agent in patients receiving ECTtreatments. Eight studies reported lack of improvement with Ketamine compared to thecontrol group. In six of these studies, Ketamine was used as an antidepressant in patientsreceiving ECT treatment [15,33–37]. Common reasons for lack of efficiency were citedas ECT ceiling treatment effect and ECT blunting the response to Ketamine. Otherreasons include inadequate sample size [38], trauma from breast cancer and surgicaltreatment of breast cancer [26]. It is noteworthy that Ketamine resulted in faster im-provement [36]. Intravenous Ketamine was ineffective for prevention of postpartumdepression [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 threetimes a day [42] reporting significant improvement in both studies. Loo and colleagues (2016)compared Ketamine administered intravenously, intramuscularly, and subcutaneously to thecontrol 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 negativecorrelation with depression [43]. Similar results were reported in a study comparing Ketamineand ECT to ECT and methohexital group, indicating BDNF as a potential biomarker forantidepressant response [31]. However, BDNF genotype was not indicated as a predictor ofresponse.
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. Ventricularectopic rhythm was reported in one study [28]. One study reported suicidal ideations andattempt [10].
Quality Assessment of RCTs
Random sequence generation was at low risk among 26 studies and allocation concealmentamong 26 RCTs. Frequency of studies reporting a low risk across other domains of Cochranerisk of bias tool was: blinding of outcome assessors (n = 30), blinding of participants andpersonnel (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 matricesof 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 acrossall matrices of Cochrane risk of bias tool. Figure 3. presents study-wise risk of bias across allmatrices 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 MDDwith chronic and treatment-resistant course. Overall, twenty-six studies (77%) reported sig-nificant improvement in depressive symptoms among patients receiving Ketamine comparedto the control group. Of the remaining eight studies, participants received ECT in five studiesin both the treatment and control group. Oral and intranasal Ketamine were effective in twoand three studies, respectively. It is noteworthy that one study comparing ECT to Ketaminereported similar improvement in both groups [32]. However, Ketamine was not found to beeffective for the prevention of postpartum depression [18]. Ketamine was associated withhigher BDNF levels in patients with MDD compared to the control group and this higherBDNF had a negative correlation with depression scores [31,43].
In the majority of studies (21/30), IV Ketamine was effective for treatment of unipolardepression and ineffective in prevention of postpartum depression in one study [18]. Theexisting 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 andNumber Needed to Treat (NNT) of ≤6 after 24 h, 3 days and 7 days [44]. The clinical responsefor Ketamine was reported at OR of ≥4.87 and NNT of ≤4 [44]. The clinical applicability ofKetamine is limited by shorter duration of action that can be challenging in patients withchronic and treatment- resistant depression. The existing evidence suggests that the clinicalresponse is observable in 40 to 120 min in about 50% of patients. However, this responselasted for two hours (51.1% Ketamine group VS 2% control group), one day (52.6% Ketaminegroup VS 7% control group), three days (46.6% Ketamine group VS 7.1% control group), andseven days (31% Ketamine group VS 7% control group) according to a pooled analysis ofseven RCTs [45]. The odds ratio for treatment response was clinically significant at day sevenwith Ketamine in patients with unipolar depression [45]. The effects of Ketamine dissipated atday 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 contextof multiple infusions of Ketamine. In this review, 13 studies administered multiple infusions ofIV Ketamine with improvement in six studies. Out of the remaining seven studies with nosignificant benefits for Ketamine group, participants received ECT in addition to IV Ketaminein five studies. The results posit discussion of two clinical questions: Ketamine as a potentantidepressant option in combination with ECT and efficacy of multiple infusions of IVKetamine.
The lack of effectiveness of Ketamine in combination with ECT can be attributed to ECTtreatment ceiling and blunting of response [37]. A meta-analysis reported that Ketamineaugmentation of ECT resulted in a significantly greater reduction in depressive symptoms atfirst 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 Ketaminewhen 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 withchronic 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 doseKetamine (0.5 mg/kg, three times on three test days) were equally effective in improvingdepression scores compared to ECT [32]. This effect was observable at 72 h and one weekafter 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. Theseresults should be carefully considered in the context of smaller sample size and titrationmethod 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 robuststudy 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 effectwith lesser risk of side effects but a slower pace of action than IV Ketamine. This conclusionwas drawn from a systematic review of two RCTs, one open-label trial, five retrospective chartreviews, 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 forEsketamine 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 ofadministration and dosage [51]. The most frequently prescribed dose of IV Ketamine is0.5 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 ofKetamine 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 deliriumin about 6% to 12% of patients [51]. Patients receiving Ketamine require close monitoring ofvital signs and cardiac status. It is also essential to monitor for neuropsychiatric functioning inthe clinic for return to baseline function [52].
This systematic review has several strengths. An electronic search of academic databasescombined with manual searching for references provides an exhaustive search for relevantevidence. It provides an overview of RCTs of Ketamine in comparison to other treatmentoptions. 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 10studies while interpreting the results of these studies.
Conclusion
Ketamine is an effective treatment option for patients with MDD with considerable adversewhen administered via IV, IN and oral routes. The dose range for IV Ketamine ranges between0.5 mg/kg to 1 mg/kg, 28–84 mg for IN dose, and oral dose ranging from 50 mg daily to threetimes a day. It is noteworthy that Ketamine was equally effective compared to ECT with afaster response among patients who received Ketamine. Ketamine argumentation of ECTneeds to be explored further in well-designed studies of adequate sample size. The short-livedantidepressant 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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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 onneurodevelopmental disorders, specifically autism spectrum disorder, and the impact of substances and traumaduring childhood. He will be applying for child and adolescent psychiatry fellowship after completion of generalpsychiatry 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 theUniversity of Kansas Medical Center. He is boardcertified in child and adolescent psychiatry, as well as adultpsychiatry. He also completed Master of Public Health degree from Benedictine University in Illinois. He earnedhis medical degree from Nishtar Medical College in Multan, Pakistan, and received his training in adultpsychiatry at Griffin Memorial Hospital in Norman, Oklahoma. He also completed his training in child andadolescent psychiatry at the University of Kansas Medical Center. Dr. Sadiq Naveed is Honorary ResearchFellow at Human Development Research Foundation of Pakistan. He is also completing his postgraduate coursein 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 andkeenly interested in pursuing her career in psychiatry.
Ania Fida graduated from King Edward Medical University, started Psychiatry Residency in Pakistan thenmoved 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 July2020.
Noureen Abbas, MD, graduated from Fatima Memorial Hospital College of Medicine & Dentistry. She iscurrently working as a research assistant. She will be starting a residency physician at Cahaba- University ofAlabama 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 interestsinclude mood disorder, and schizophrenia.
Zheala Qayyum, MD. MMSc is the Assistant Clinical Professor of Psychiatry at Yale School of Medicine. Sheis board certified in general psychiatry, child and adolescent psychiatry and consultation liaison psychiatry. Shealso completed her Master of Medical Science in Medical Education from Harvard Medical School. She iscurrently the Program Director for the Child and Adolescent psychiatry fellowship at Boston Children’s Hospitaland faculty at Harvard Medical School. Her interests included early onset psychosis, supporting mental health ofLGBTQ youth, psychoncology and palliative care in children and adolescents. Additionally, her researchinterests lie in the supervision of trainees in the event of patient death by suicide.
Psychiatric Quarterly
Affiliations
Raheel Imtiaz Memon1& Sadiq Naveed2
& Amber Ehsan Faquih3& Ania Fida4 & Noureen
Abbas5 & Amna Mohyud Din Chaudhary6 & Zheala Qayyum7
Raheel Imtiaz [email protected]
Amber Ehsan [email protected]
Ania [email protected]
Noureen [email protected]
Amna Mohyud Din [email protected]
Zheala [email protected]
1 Resident Physician, Henry Ford Allegiance Health, Jackson, MI, USA2 University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, USA3 Dow University of Health Sciences, Karachi, Pakistan4 King Edward Medical University, Lahore, Pakistan5 FMH College of Medicine & Dentistry, Lahore, Pakistan6 Nishtar Medical University, Multan, Pakistan7 Boston Children’s Hospital, Boston, MA, USA
Psychiatric Quarterly
