Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression.

Abstract

BACKGROUND: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. METHODS: Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. RESULTS: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. CONCLUSIONS: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.

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ARCHIVAL REPORT
Rapid and Longer-Term Antidepressant Effects of
Repeated Ketamine Infusions in Treatment-Resistant
Major Depression
James W. Murrough, Andrew M. Perez, Sarah Pillemer, Jessica Stern, Michael K. Parides,
Marije aan het Rot, Katherine A. Collins, Sanjay J. Mathew, Dennis S. Charney, and Dan V. Iosifescu
Background: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of
ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD)
foundthatsixketamineinfusionsresultedinasustainedantidepressanteffect.Inthecurrentreport,weexaminedthepatternanddurability
of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original.
Methods: Participants with TRD (n ? 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions
of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were
monitored for relapse for up to 83 days from the last infusion.
Results: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery–Åsberg Depression Rating
Scale score at 2 hours after the first ketamine infusion (18.9 ? 6.6, p ? .001), and this decrease was largely sustained for the duration of the
infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders,
median time to relapse after the last ketamine infusion was 18 days.
Conclusions: KetaminewasassociatedwitharapidantidepressanteffectinTRDthatwaspredictiveofasustainedeffect.Futurecontrolled
studieswillberequiredtoidentifystrategiestomaintainanantidepressantresponseamongpatientswhobenefitfromacourseofketamine.
KeyWords:Antidepressant,experimentaltherapeutics,glutamate,ket-
amine,majordepressivedisorder,treatment-resistantdepression
M
sant treatments (1–3). Against this background, reports of a
rapid-onset antidepressant effect associated with the N-methyl-
D-aspartate glutamate receptor antagonist ketamine have gen-
erated considerable interest among both clinicians and re-
searchers (4–7). Notably, rapid antidepressant effects are
observed even in individuals who have failed to respond to
previous treatment attempts. This group of patients can be de-
scribed as suffering from treatment-resistant depression (TRD),
and as a group, they suffer more severe depressive symptoms,
exhibit more illness-related disability, and experience a more
chronic or relapsing course of illness compared with their non-
TRD counterparts (8,9).
ajordepressive disorder (MDD) is associated with a very
high degree of morbidity and public health cost, in part
due to the limited effectiveness of current antidepres-
The large majority of clinical research involving ketamine in
depression has focused on the safety and efficacy of a single low-
dose (.5 mg/kg) IV infusion (4–6). An initial placebo-controlled,
double blind crossover study in inpatients with major depression
reported a large mean reduction in depression severity (14 ? 12
points on the 25-item Hamilton Depression Rating Scale) 72 hours
after a single ketamine infusion (4). A second study using a similar
design reported a rapid antidepressant effect within 2 hours and a
71% response rate at 24 hours (5). In total, four placebo-controlled
studies of a single ketamine infusion in unipolar or bipolar depres-
sion support the rapid antidepressant effects of ketamine in mood
disorders (4,5,10,11).
Mostindividualswhorespondtoketamineexperiencearelapse
within several days or up to 1 week, although there is considerable
variability in time to relapse after a single infusion (5,12,13). A par-
amountclinicalissue,therefore,istoidentifyastrategytomaintain
the antidepressant effects of ketamine (7,14). To begin to address
this question, our group previously reported on the safety and
efficacyofuptosixinfusionsofketamineovera12-dayperiodin10
patientswithTRD(15).Inthatstudy,ketaminewasfoundtobesafe
and well-tolerated.
In the current study, we sought to extend the findings of our
previous study (15) to further characterize the pattern of change
in depressive symptoms and durability of response in the con-
text of repeated ketamine infusions in a larger sample of sub-
jectswithTRD(inclusiveofparticipantsfromtheoriginalreport).
Specifically, we: 1) measured the overall proportion of response
after up to six ketamine infusions; 2) determined the time-point
associated with the largest change in symptom severity; 3) com-
pared the trajectory of symptom change between study re-
sponders and nonresponders; 4) estimated time to relapse
among responders after cessation of ketamine, and 5) investi-
gated the effects of ketamine on individual symptoms of
depression.
From the Mood and Anxiety Disorders Program (JWM, SP, JS, DSC, DVI),
Department of Psychiatry; Department of Neuroscience (JWM, KAC,
DSC, DVI); Department of Anesthesiology (AMP); Center for Biostatistics
(MKP), Department of Health Evidence and Policy; Department of Phar-
macology and Systems Therapeutics (DSC); Office of the Dean (DSC),
Mount Sinai School of Medicine, New York, New York; Experimental
Psychopathology Program (MahR), Department of Psychology; School
of Behavioral and Cognitive Neuroscience (MahR), University of Gro-
ningen, Groningen, the Netherlands; Department of Psychiatry and Be-
havioral Sciences (SJM), Baylor College of Medicine; and the Michael E.
Debakey VA Medical Center (SJM), Houston, Texas.
Address correspondence to James W. Murrough, M.D., Mood and Anxiety
Disorders Program, Department of Psychiatry, Mount Sinai School of
Medicine,1GustaveL.LevyPlace,Box1230,NewYork,NY10029;E-mail:
james.murrough@mssm.edu.
Received May 3, 2012; revised Jun 13, 2012; accepted Jun 20, 2012.
BIOL PSYCHIATRY 2012;xx:xxx
© 2012 Society of Biological Psychiatry
0006-3223/$36.00
http://dx.doi.org/10.1016/j.biopsych.2012.06.022

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Methods and Materials
Participants
Study participants were recruited from physician referrals, me-
dia advertisement, or an academic outpatient psychiatric clinic.
Participants had chronic or recurrent MDD that was the primary
presenting problem as assessed by a trained rater with the Struc-
tured Clinical Interview for DSM-IV (16) and a diagnostic interview
with a study psychiatrist. To be eligible, participants had to have
failedtorespondtoatleasttwoU.S.FoodandDrugAdministration-
approved antidepressant medications in the current episode ac-
cording to the Antidepressant Treatment History Form (17). If a
participant was taking antidepressant medication at the time of
screening, a washout of ?2 weeks (or 4 weeks for fluoxetine) was
requiredbeforeenrollment,andparticipantsremainedfreeofanti-
depressant medication throughout the infusion period. Additional
inclusion criteria included a score of ? 32 on the Inventory of
Depressive Symptomatology—Clinician Rated (IDS-C) (18) at
screen and baseline and a negative urine toxicology screen. Exclu-
sion criteria included uncontrolled hypertension, any unstable
medical condition, any Axis I disorder other than MDD that was
judged to be the primary presenting problem, substance abuse or
dependence in the 3 months before screen, lifetime history of psy-
chosis,anypsychoticdisorder,bipolardisorder,developmentaldis-
order, or recreational use or abuse of ketamine or phencyclidine.
Physical examination, vital signs, weight, electrocardiogram, stan-
dard blood tests, and urinalysis confirmed absence of unstable
medical illnesses. Women of childbearing potential were required
to have a negative pregnancy test before enrollment.
The Mount Sinai School of Medicine Institutional Review Board
approved the study, and written informed consent was obtained
from all subjects before participation. The study is registered at
http://ClinicalTrials.gov (NCT00548964).
Study Procedures and Rating Instruments
The study consisted of two phases. In phase I, participants re-
ceived up to six IV infusions of ketamine (.5 mg/kg) on a Monday-
Wednesday-Friday schedule over a 12-day period. In phase II, par-
ticipants who met response criteria after the last dose of ketamine
inphaseIwerefolloweduntilrelapseorforthemaximumfollow-up
time of 83 days, whichever came first. Response in phase I was
definedasa?50%improvementindepressivesymptomsasmea-
sured by the Montgomery–Åsberg Depression Rating Scale
(MADRS) (19). Relapse in phase II was defined as ?50% improve-
ment in MADRS score at that visit compared with baseline for two
consecutive visits.
Results from the first 10 participants enrolled in the current
study were previously reported in part, and the methods for the
current report are very similar to what was described therein
(15). Briefly, participants were admitted to the Mount Sinai Clin-
ical Research Unit on the morning of the first infusion for a
24-hour stay to optimize safety and monitoring. All subsequent
infusions occurred as an outpatient procedure at the Clinical
Research Unit. An anesthesiologist (A.M.P.) administered race-
mic ketamine hydrochloride (Bedford Laboratories, Bedford,
Ohio) diluted in normal saline over 40 min by IV infusion pump
with standard telemetry monitoring. In the first cohort, partici-
pants were exited from the study if they failed to achieve re-
sponse after the first infusion (this occurred in one case among
the n ? 10) (15). The protocol was subsequently changed to
allow participants to remain in the study regardless of response
status after the first infusion (n ? 14) to measure the effect of
repeated ketamine infusions among initial nonresponders.
The primary outcome for phase I was change in depressive
symptoms measured by the MADRS over the 12-day infusion pe-
riod. Depression severity was measured in the morning before the
firstketamineinfusion(?60min)andthenat?120min,?240min,
and 24 hours. Depression severity was measured at ?60 min and
?240minforeachsubsequentinfusionday.Responderstatusafter
the sixth infusion or the last observation for noncompleters was
usedtodetermineoverallphaseIresponderstatus.DuringphaseII,
responders were followed twice weekly for 4 weeks, then every
otherweekfor8weeksoruntilrelapse,whichevercamesooner.All
but two participants remained free of antidepressant medication
forthedurationofthefollow-upperiod.Threeofthe17responders
wereenrolledinaseparaterelapsepreventionstudyofvenlafaxine
extended-release (ER) up to 300 mg daily during the follow-up
period (two were randomized to medication, one was randomized
to placebo).
Acute dissociative and psychotomimetic effects of ketamine
weremeasuredbeforethestartofeachinfusion,duringorimmedi-
ately upon completion of each infusion (?40 min), and then ?240
min after infusion. Psychotomimetic effects were measured with
the four-item positive symptom subscale of the Brief Psychiatric
RatingScale(BPRS)(scalerange4–28)(20);dissociativeeffectswere
measuredwiththeClinician-AdministeredDissociativeStatesScale
(scale range 0–92) (21); manic-like mood elevation was measured
with the mood item of the Young Mania Rating Scale (scale range
0–4) (22); a feeling of being “high” was measured with a Visual
Analog Scale (range 0–10). General side effects were measured
with the Systematic Assessment For Treatment Emergent Effects
Self-ReportInventory(23)administeredinthemorningbeforeeach
infusion and then immediately upon completion of the infusion
(?40 min) and at ?240 min.
Guidelines established for clinically significant changes in vital
signs during the ketamine infusions were as follows: systolic or
diastolic blood pressure (BP) ?180/100 or ?20% increase above
pre-infusion reading or tachycardia ?110 beats/min. The infusion
wasdiscontinuedintheeventthatsignificantchangesinvitalsigns
occurredthatdidnotrespondtomedicationintervention(seeSup-
plement 1 for details).
Statistical Analysis
Baseline characteristics were compared between responders
and nonresponders with the Mann-Whitney U test for continuous
variablesandthe?2testforcategoricalvariables.Changesbetween
two time-points for continuous variables were tested with paired t
tests, and associations between continuous variables were quanti-
fied with the Spearman correlation coefficient. Random effects
models were used to summarize and quantify changes in the
MADRS score and its component items over time and to compare
temporal differences between eventual responders and nonre-
sponders.Splineswereusedtodeterminedifferencesinthepattern
ofresponseovertimeamongallpatientsandtoidentifythetimeat
which there was no additional improvement in depressive symp-
toms.Additionally,therelationshipbetweenresponsestatusat2,4,
and24hoursafterbaselineandendofstudywassummarizedwith
sensitivity, specificity, and positive and negative predictive values.
Timetorelapseforpatientswhometresponsecriteriaattheendof
phase I was estimated with the Kaplan-Meier method. Analyses
wereperformedwithIBMSPSSStatistics(version19;SPSS,Chicago,
Illinois) and SAS (version 9.2; SAS, Cary, North Carolina).
Results
Twenty-four participants received at least one ketamine infu-
sion. Twenty-two participants received at least two infusions, and
2 BIOL PSYCHIATRY 2012;xx:xxx
J.W. Murrough et al.
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Page 3

21 participants received all six scheduled ketamine infusions.
Amongthethreeparticipantswhodidnotreceivethefullschedule
of ketamine infusions: one was exited after one infusion due to
nonresponseasperprotocolforthefirstcohort(seeMethods);one
experienced hemodynamic elevation during the first infusion re-
sulting in study exit as per protocol (see Methods and Hemody-
namic Changes sections); and one withdrew consent after three
infusionsduetoperceivedlackofresponseanddesireforstandard
treatment.
Baseline Characteristics
Demographicandclinicalcharacteristicsofthestudysampleare
presentedinTable1.Participantswere48.1?13.0yearsofagewith
an age of onset of MDD of 22.8 ? 13.6 years and had failed to
respond to 6.1 ? 3.3 antidepressant treatment trials and 2.3 ? 2.3
augmentation trials in the current major depressive episode.
Phase I: Time-Course of Antidepressant Effects of Ketamine
The overall response rate at study end was 70.8% (17 of 24
participants). Within 2 hours of the first dose of ketamine, there
was a large and statistically significant mean improvement in
MADRS score from baseline to 2 hours across the full study
sample: 18.9 ? 6.6 (decrease from 31.8 to 12.9, p ? .001)
(Figure 1).
The large magnitude of the 2-hour response was generally
maintained over the infusion period as estimated by a random
Table 1. Demographic and Clinical Characteristics of Total Study Sample and Responder/Nonresponder Subgroups
Total SampleResponder Subgroup Nonresponder Subgroupp
Participants, n (%)
Gender (M/F)
Age at Enrollment (yrs)
Education (yrs)
Age at Onset of MDD (yrs)
Length of Current Episode (yrs)
Lifetime Episodes, n
First-Degree Relative with Mood Disorder, n (%)
Failed Antidepressants (Current Episode)a, n
Failed Antidepressant Augmentations (Current Episode)a, n
Lifetime History of ECT, n (%)
Lifetime History of Suicide Attempt, n (%)
Past Substance Use Disorder, n (%)
Current Anxiety Disorder, n (%)
Current Pain Disorder, n (%)
Baseline MADRS Score
Baseline IDS-C Score
24 (100%)
15/9
48.1 ? 13.0
16.0 ? 2.5
22.8 ? 13.6
18.1 ? 16.8
1.8 ? 1.1
14 (58.3%)
6.1 ? 3.3
2.3 ? 2.3
4 (16.7%)
3 (12.5%)
8 (33.3%)
6 (25%)
3 (12.5%)
31.8 ? 6.1
44.0 ? 9.8
17 (71%)
10/7
48.9 ? 11.8
15.2 ? 2.7
26.4 ? 14.2
17.0 ? 16
1.7 ? .9
10 (58.8%)
6.1 ? 3.6
2.4 ? 2.2
2 (11.8%)
1 (5.9%)
5 (29.4%)
4 (23.5%)
2 (11.8%)
31.6 ? 6.3
45.1 ? 10.5
7 (29%)
5/2
46.1 ? 16.5
17.1 ? 1.0
14.0 ? 6.8
20.6 ? 19.4
2.0 ? 1.5
4 (57.1%)
6.0 ? 2.7
2.0 ? 2.5
2 (28.6%)
2 (28.6%)
3 (42.9%)
2 (28.6%)
1 (14.3%)
32.1 ? 6.2
41.6 ? 8.1
—
.56
.73
.016
.039
.74
.89
.94
.70
.65
.32
.13
.53
.80
.87
.63
.46
ThepvaluesresultfromMann-WhitneyUor?2testscomparingstudyphaseIresponderandnonrespondersubgroups.Statisticalsignificancewasdefined
at the .05 level, two-tailed.
ECT, electroconvulsive therapy; F, female; IDS-C, Inventory of Depressive Symptomatology—Clinician Rated; MADRS, Montgomery–Åsberg Depression
Rating Scale; M, male; MDD, major depressive disorder.
aOnly includes failed trials with a score ?3 according to the Antidepressant Treatment History Form.
0 2hr4hr24hr
4679 1113
358 10 12
0
10
20
30
40
50
Time (Days)
MADRS Score
Phase I
Responders
(n=17)
Phase I Non-
Responders
(n=7)a
Ketamine 0.5 mg/kg IV
*
*
*
**
**
*
*
**
**
*
*
*
#
#
# #
#
##
# #
# #
Figure 1. Change in depression severity after repeated ketamine infusions in treatment-resistant major depression. Figure depicts change in depression
severityasmeasuredbytheMontgomery–ÅsbergDepressionRatingScale(MADRS)(mean?SD)overa12-dayperiodduringwhichketamine(.5mg/kg)was
administeredIVonaMonday-Wednesday-Fridayschedule,correspondingtostudydays0,3,5,8,10,and12.Trajectoriesofdepressionseverityareplottedfor
phaseIresponderandnonrespondersubgroups,definedwiththefinalobservedMADRSscore.Depressionseveritywasinitiallymeasuredatbaselinebefore
the first ketamine infusion and then at 2, 4, and 24 hours while participants were inpatients. Subsequent infusions occurred on an outpatient basis, and
depression severity was measured in the morning before each infusion and then at 4 hours. *MADRS score significantly decreased at given time point
compared with baseline, p ? .05.#MADRS score significantly different at given time point between responder and nonresponder subgroups.aThree
participants in the nonresponder group did not receive all six ketamine infusions.
J.W. Murrough et al.
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Page 4

effectsmodel:averagedailydecreaseinMADRSscoreof.128?.17
(p ? .45). Phase I responders continued to improve slightly but
significantly after the initial 2-hour improvement (average daily
decrease in MADRS score of .35 ? .10, p ? .004), whereas phase I
nonresponderstendedtoworsenovertime(averagedailyincrease
in MADRS score of .78 ? .40, p ? .096).
The separation of responders from nonresponders was clearly
evident by 4 hours (MADRS score 10.35 ? 5.74 vs. 19.0 ? 6.46, p ?
.013) and was large at 24 hours (8.35 ? 4.2 vs. 18.8 ? 5.5, p ? .002)
(Figure 1). Ninety-four percent of study responders had responded
by 4 hours (i.e., sensitivity was 94%), as did 29% of nonresponders
(i.e., specificity was 71%), with positive and negative predictive
values of .89 and .83, respectively (Table 2). The relative risk of
overall study nonresponse for 2-hour nonresponders was 4.0 (95%
confidence interval: 1.23–12.99).
Phase I: Effect of Ketamine on Individual Symptoms of
Depression
Within 2 hours of the first dose of ketamine, there was a signifi-
cantreductionineachindividualMADRSitemscorecomparedwith
baselineacrossthefullstudysample(p?.01;withtheexceptionof
theappetiteandsleepitemsthatwerenotexaminedatthe2-hour
time-point)(Figure2).Thenonrespondersubgroupmanifestedsig-
nificant reductions in reported sadness, inner tension, pessimistic
thoughts, and suicidal thoughts but not the other items (p ? .05)
(Figure2).ThelargestdifferenceinmagnitudebetweenthephaseI
responders and nonresponders at 2 hours was change in lassitude
(Cohen’s d ? 1.34). The observed difference between decrease in
apparent sadness and concentration difficulty between the re-
sponderandnonrespondersubgroupswasalsolarge(Cohen’sd?
.88 and .96, respectively).
Phase II: Risk of Relapse After Response to Ketamine
The 17 phase I responders were followed for up to 83 days to
estimatetimetorelapse(Figure3).Themediantimetorelapsewas
18 days, and the 24th and 75th percentiles were 11 and 27 days,
respectively. Four participants did not relapse, and the estimated
riskofremainingrelapse-freeforupto83daysis.25?.11.Fourteen
individuals received no psychotropic medication during the fol-
low-up period, whereas 3 individuals participated in a placebo-
controlled study of venlafaxine ER for relapse prevention after ket-
amine (Methods). The relapse experience of the three participants
receiving psychotropic medication was similar to the other re-
sponders: of the two participants randomized to venlafaxine ER,
one relapsed at day 20, and one was a responder at day 83. The
participantrandomizedtoplaceboafterketaminewasalsorelapse-
free at day 83.
Acute Dissociative and Psychotomimetic Effects Associated
with Ketamine
Ketaminewasassociatedwithasmallbutsignificantincreasein
psychotomimetic symptoms as measured by the BPRS (increase
fromameanof4.0?.1beforeinfusionto4.5?.9atthepeakofthe
0
Absolute Decrease in MADRS Item Score
1234
Apparent Sadness
Reported Sadness
Inner Tension
Concentration Difficulties
Lassitude
Inability to Feel
Pessimistic Thoughts
Suicidal Thoughts
MADRS Items
Total Sample
Phase I Responders
Phase I Non-Responders
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
#
#
Figure 2. Change in individual depressive symptoms 2 hours after the first
infusionofketamine.Figuredepictsabsolutedecreaseinindividualitemsof
the Montgomery–Åsberg Depression Rating Scale (MADRS) from baseline
to 2 hours after the first infusion of ketamine for the total sample, phase I
responders and nonresponders. The score of each item of the MADRS
ranges from 0 (no symptom) to 6 (maximally severe symptom). Bars repre-
sentmeans?SEM.*Itemscoresignificantlydecreasedat2-hourtimepoint
compared with baseline, p ? .05.#Change in item score from baseline to 2
hours significantly different between responder and nonresponder sub-
groups.
010 20 30 405060 70 80
0
10
20
30
40
50
60
70
80
90
100
Time (Days)
Probability of Relapse (%)
Figure3.Riskofrelapseamongresponderstorepeatedketamineinfusions
in treatment-resistant major depression. Figure depicts survival analysis
conducted in 17 phase I responders after six infusions of ketamine (maxi-
mum follow-up time ? 83 days). Relapse in phase II was defined as ?50%
improvementinMontgomery–ÅsbergDepressionRatingScalescoreatthat
visit compared with baseline for two consecutive visits.
Table 2. Diagnostic Test Statistics Considering the Validity of Early
Antidepressant Response Predicting End of Study Response During
Repeated Ketamine Infusions in Treatment-Resistant Major Depression
Hours SensitivitySpecificity PPVNPV
2
4
24
.65
.94
.88
.57
.71
.71
.79
.89
.88
.40
.83
.71
Tablereportsstatisticsofsensitivity,specificity,positivepredictivevalue
(PPV), and negative predictive value (NPV) considering response status at
the 2-, 4-, and 24-hour time points after the first dose of ketamine as a
diagnostic test for predicting subsequent phase I response. See text for
details.
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infusion, p ? .013). The BPRS score returned to a mean of 4.0 by
?240 min after infusion. Ketamine resulted in a mild, significant
increase in dissociative symptoms as measured by the Clinician-
Administered Dissociative States Scale (increase from a mean of
.3?.5beforeinfusionto7.8?12.0atthepeakoftheinfusion,p?
.001), which returned to baseline by ?240 min after infusion. A
similarpatternwasobservedforelevatedmoodasmeasuredbythe
Young Mania Rating Scale-1 (p ? .002) or the Visual Analog Scale
High (p ? .001). There was no trend toward increasing dissociative
orpsychotomimeticeffectsoverthecourseofthetrial.SeeTableS1
in Supplement 1 for details.
There was no difference in dissociative, psychotomimetic, or
highfeelingbetweenrespondersandnonrespondersoranycorre-
lation between change in MADRS score and change in any of the
acute measures across the infusion period.
General Side Effects
Generalsideeffectsweremeasuredinthemorningbeforeeach
infusion and then immediately upon completion of the infusion
(?40 min), at ?120 min and at ?240 min (Table S2 in Supplement
1). The most commonly reported side effects during the 4-hour
period after each infusion included feeling strange or unreal
(58.3%), abnormal sensations (54.2%), blurred vision (50.0%), and
feelingdrowsyorsleepy(45.8%).Thesesideeffectswerelargelynot
reported at the morning pre-infusion assessments for infusions
2–6, suggesting the transient nature of the side effects. Notably,
onlyfourparticipants(16.7%)reportedthatanysideeffectimpaired
functioning at any time during the study.
Hemodynamic Changes
Sixteen participants (67%) did not experience any clinically sig-
nificant change in vital signs during any of the ketamine infusions.
Eightparticipants(33%)experiencedelevatedBPand/orheartrate
according to pre-defined study criteria at least once during the
series of infusions (see Methods section and Supplement 1). One
participant experienced elevated BP during the first infusion that
didnotrespondsatisfactorilytoadministrationofantihypertensive
medication, resulting in discontinuation of the infusion and study
exit (maximum BP: 180/115). The BP of that participant stabilized
shortly after discontinuation of the ketamine infusion. No serious
adverse events occurred during the study.
Discussion
Herein we report the results of the largest study conducted to
date on the antidepressant effects of repeated ketamine infusions
in TRD. The major findings of this study are that: 1) the antidepres-
sant effect of ketamine is evident very early in the course of treat-
ment, 2) ketamine exerts a broad-spectrum effect on individual
symptomsofdepression,and3)rapidresponsetothefirstinfusion
is highly predictive of a sustained response to subsequent infu-
sions.
An initial infusion of ketamine was associated with a large anti-
depressanteffect(MADRSscoredecreased18.9?6.6frombaseline
to 2 hours), and this effect was generally maintained throughout
thecourseofuptofiveadditionalinfusions.Theeffectofketamine
was observed across nearly the full spectrum of depressive symp-
toms in the total study sample. Of particular note, suicidal ideation
(SI) rapidly decreased across the total study sample, even among
study nonresponders. Although preliminary, this result suggests
that ketamine might exert a unique anti-SI effect even in the ab-
sence of a full response and is consistent with previous reports
highlighting the potential anti-SI effects of ketamine in depressed
populations (10,24,25).
We found that antidepressant response very early in the course
oftreatmentwithketaminestronglypredictedsubsequentantide-
pressantresponse.Specifically,responsestatusat4hourswas94%
sensitiveand71%specificforpredictingresponsestatusattheend
of phase I. Although preliminary, these findings suggest that pa-
tients who will benefit from a course of repeated ketamine infu-
sions will manifest a rapid improvement in depression that is then
maintainedoverthecourseoftreatment.Conversely,lackofarapid
response is a poor prognostic indicator for improvement after ad-
ditional ketamine infusions. These data are in contrast to the time-
courseofresponsetostandardantidepressants.Forexample,inthe
first step of the STAR*D (Sequenced Treatment Alternatives to Re-
lieve Depression) study, 56% of participants who responded at
some point during a 12-week trial of the serotonin selective re-
uptake inhibitor citalopram did so only at or after 8 weeks of treat-
ment (26). Other groups, however, have reported that improve-
ments within a few weeks of initiating standard antidepressant
treatment are predictive of a later stable response (27,28). A more
definitiveconclusionwithregardtothevalidityofearlyresponseto
ketamine predicting a more durable response must await the re-
sults of future controlled studies.
After the final ketamine infusion, the observed median time to
relapseamongresponderswas18days,andtherewasconsiderable
inter-subject variability (range 4 to ?83 days). Characterizing the
durability of antidepressant response after ketamine is a critical
issue in determining the potential clinical utility of ketamine as a
treatment for TRD. Initial reports suggested a duration of response
ofseveraldaysorupto1weekafterasingleketamineinfusion(5).A
recent study of a single ketamine infusion in bipolar depression
foundatimetorelapseofjust2dayswiththeKaplan-Meiermethod
(11).Thefindingsofthecurrentstudymightthereforesuggestthat
repeated infusions yield a more durable antidepressant response
compared with a single infusion, even after the infusions are dis-
continued. Interestingly, in a previous placebo-controlled study of
riluzole for relapse prevention after a single administration of ket-
amine we observed a mean time-to-relapse of 22 and 24.4 days for
placebo or riluzole, respectively (6). This difference was not signifi-
cant in part due to the unexpectedly long time-to-relapse of the
placebogroup(6).Asecondstudyofriluzoleforrelapseprevention
after ketamine reported a time-to-relapse of 9.8 and 17.2 days for
placebo and riluzole, respectively (12). Taken together, the data
from the current study provide preliminary evidence for an en-
hanced durability of response after repeated ketamine infusions
butalsohighlightstheneedtoidentifyeffectiverelapseprevention
strategies for patients who respond to ketamine.
Future studies testing relapse prevention strategies after re-
sponsetoketaminemightbeguidedbyhypothesizedmechanistic
synergy. Although the riluzole for relapse prevention strategy was
based on potential synergy between ketamine and riluzole involv-
ing modulation of glutamate signaling, the recent identification of
additional signaling pathways implicated in the antidepressant ac-
tion of ketamine suggests new targets for synergy (7,29–31). In
particular,thefindingthatinhibitionofglycogensynthasekinase-3
is obligatory for the antidepressant effect of ketamine in mice (31)
suggests lithium—a well-known inhibitor of glycogen synthase
kinase-3—as a potential pharmacotherapeutic strategy after ket-
amine.
With regard to side effects observed in this study, dissociative
andpsychotomimeticchangesassociatedwithketaminewereonly
present acutely (during and immediately after infusions) and were
generally mild and well-tolerated. We observed an expected in-
creaseindissociativesymptomsduringadministrationofketamine
thatreturnedtobaselinewithin4hoursofthestartoftheinfusion.
J.W. Murrough et al.
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At no time did any participant evidence clinically significant psy-
chotomimeticeffectsresultingfromketamine(e.g.,paranoid,delu-
sions, hallucinations). Other adverse effects were generally mild,
and no individual discontinued study participation due to side ef-
fects. Importantly, there was no evidence of increasing severity of
theseeffectsoverthe12-dayinfusionperiod.Therewasnocorrela-
tion between acute dissociative or psychotomimetic effects of ket-
amine and antidepressant treatment response.
Overall, our results suggest that repeated ketamine infusions
might be a viable treatment strategy in the future for patients
suffering from TRD. A strategy involving repeated ketamine infu-
sions is currently being investigated as treatment for chronic pain
disorders in ambulatory patients that might provide a model for
ketamine treatment in TRD in the future (32). Concerns persist,
however, with regard to the safety and feasibility of prolonged
treatment with ketamine and the optimal number of repeated
treatments for safety and efficacy purposes. More preclinical and
clinicalresearchwillberequiredbeforethistreatmentstrategycan
berecommended(33,34).Chiefamongourconcernsareaseriesof
early preclinical studies showing that repeated administrations of
very high doses of ketamine or other N-methyl-D-aspartate recep-
torantagonistsmightbeneurotoxicinrodents(35,36).Neuroimag-
ingstudiesinhumanpopulationssuggestthatprolongedabuseof
ketamineasanillicitdrugmightresultindeleteriousbrainchanges
(37,38),althoughthesestudieshavebeencross-sectionalinnature
and are confounded by significant comorbid substance abuse be-
yond ketamine. Research investigating the role of ketamine in TRD
mustbalanceconcernsregardingpotentialtoxicityagainsttheun-
met need for rapidly acting, more effective treatments for patients
suffering from enormous morbidity and disability.
Our study has several limitations. Most notably, the open-label
design limits the interpretation of efficacy. Specifically, it is not
knowntowhatextenttheobserveddecreaseindepressionseverity
would have occurred even under placebo conditions. However,
there are currently at least four placebo-controlled studies of ket-
amine in TRD or bipolar depression showing that ketamine results
in a rapid antidepressant effect superior to placebo (4,5,10,11).
Therefore, the current study was not designed to test the antide-
pressant effect of ketamine per se but rather to investigate the
pattern for response to repeated administrations of ketamine over
time.Thesecondsignificantlimitationisthemodestsamplesizeof
24 that limits the interpretations that can be drawn and the gener-
alizability of the sample to the broader population of patients with
TRD. Despite the limited sample size, however, the current report
represents the largest prospective study of repeated ketamine ad-
ministrations in TRD conducted to date. Notwithstanding the im-
portant limitations, we believe that the current report contributes
significantly to the small but growing literature on the clinical im-
pact of ketamine in patients with TRD.
TheprojectdescribedwassupportedinpartbyGrantUL1RR029887
fromtheNationalCenterforResearchResources,NationalInstitutesof
Health (NIH), and by the Brain and Behavior Research Foundation
(NationalAllianceforResearchonSchizophreniaandDepressionDis-
tinguished Investigator Award to Dr. Charney; Young Investigator
AwardtoDr.Murrough).Dr.MurroughissupportedbyaCareerAward
(K23MH094707)fromtheNationalInstituteofMentalHealth.Thecon-
tentissolelytheresponsibilityoftheauthorsanddoesnotnecessarily
representtheofficialviewsoftheNationalInstituteofMentalHealthor
theNIH.
We wish to thank Jazmin Moral, Drs. Adriana Feder, Kyle Lapidus,
Brian Iacoviello and Laili Soleimani for their assistance in participant
screening and study procedures. We wish to thank Dr. David Reich,
ChairofAnesthesiology,forhiscontinuingsupportofthisresearch.We
wish to thank the nursing staff at the Mount Sinai Clinical Research
Unitfortheirsupportandtheircareofstudyparticipants.Mostimpor-
tantly,wewishtothankallofthepatientsandtheirfamiliesforpartic-
ipatinginthisstudy.
Dr. Charney, Dean of Mount Sinai School of Medicine, has been
namedasaninventoronause-patentofketamineforthetreatmentof
depression.Ifketaminewereshowntobeeffectiveinthetreatmentof
depressionandreceivedapprovalfromtheFoodandDrugAdministra-
tion for this indication, Dr. Charney and Mount Sinai School of Medi-
cine could benefit financially. Within the past 2 years, Dr. Murrough
completed a research fellowship at Mount Sinai School of Medicine
thatwassupportedinpartbyaneducationalgrantfromAstraZeneca
toMountSinai.Dr.Iosifescuinthelast2yearshasbeenaconsultantfor
Central Nervous System Response. Lifetime, Dr. Iosifescu has received
research support from Aspect Medical Systems, Forest Laboratories,
andJanssenPharmaceutica;hehasbeenaconsultantforForestLab-
oratories, Gerson Lehrman Group, and Pfizer; and he has been a
speaker for Eli Lilly and Company, Forest Laboratories, Pfizer, and
Reed-Elsevier.Dr.Mathewhasreceivedresearchfundingorsalarysup-
port over the last 2 years from the Banner Family Fund, Brain and
Behavior Fund, The Brown Foundation, Bristol-Myers Squibb, Depart-
ment of Veterans Affairs, Evotec, Johnson and Johnson, and the Na-
tionalInstituteofMentalHealth(5R01MH81870).Hehasreceivedcon-
sulting fees or honoraria from Allergan, AstraZeneca, Cephalon,
Corcept,Roche,andTakedaandhasreceivedmedicationfromSanofi-
AventisforanNIH-sponsoredstudy.Dr.Mathewhasbeennamedasan
inventor on a use patent of ketamine for the treatment of depression.
Dr. Mathew has relinquished his claim to any royalties and will not
benefit financially if ketamine were approved for this use. Drs. Perez,
Parides and aan het Rot and Ms. Pillemer, Stern, and Collins reported
nobiomedicalfinancialinterestsorpotentialconflictsofinterest.
ClinicalTrials.gov: Continuation Intravenous Ketamine in Major
Depressive Disorder; http://clinicaltrial.gov/ct2/show/NCT00548964?
term?NCT00548964&rank?1;NCT00548964.
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