ketamine depression - oklahoma ketamine center · effects in patients with treatment-resistant...
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Contact:
Phone#:405-471-5670
Fax#:405-471-5671
Address:2916AstoriaWay
Suite150
Edmond,OK73034
Website
www.oklahomaketaminecenter.com
Hours:
Mon: 8am-4pm
Tue: 8am-4pm
Wed: 8am-4pm
Thu: 8am-4pm
Fri: 8am-4pm
Sat:closed
Sun:closed
ContactUs:
Phone#:405-471-5670
Fax#:405-471-5671
Address:2916AstoriaWay
Suite150
Edmond,OK73034
Ketamine
for
Depression
ReferenceGuideforHealth
Professionals
1
ContactUs:
Phone#:405-471-5670
Fax#:405-471-5671
Address:2916AstoriaWay
Suite150
Edmond,OK73034
Website:www.oklahomaketaminecenter.com
2
Ketaminein
theMedical
Field
OklahomaKetamineCenter
Ketamineisapopularanesthetic
drugthathasastrongaffinitytothe
NMDAreceptorsinthebrain.Itisan
FDAapproveddrugprimarilyusedin
ahospitalsetting.Atdosesof2mg/kg,
Ketamineisasafeandeffective
inductiondrugforanesthesia.
Ketamineisalsooftenusedinlabor
anddeliveryasanadjuncttospinal
anesthesiaduringacesareansection
atonetimeintravenousdoseof
30-50mg.Itisalsousedinthe
emergencydepartmentforprocedural
sedationandpainmanagement.
3
WhatKetamineTreatment
MeansforYouandYourPatient
AtOklahomaKetamine
Center,weprovidelow
ketaminesub-
anestheticdosefor
treatmentofmoderate
toseveredepression.
Fordepression
treatment,afractionof
thedosesusedina
cesareansectionisused
over50-60minutes.
Patientsdonotlose
consciousnessandoften
spendtimelisteningto
musicorontheir
phones.Therearesome
whochoosetonap
duringthetreatment.
OklahomaKetamineCenter
4
OklahomaKetamineCenter
Thereareplentyofresearcharticles
whichshowcasethesesameresults.A
fewselectedabstractsarealsoprovided
inthisinformationalbooklet.
Patientswhohavegonethroughthe
Ketaminetreatmenthaveexperienced
drasticandlonglastingreliefin
depressionsymptoms.TheBeck's
DepressionInventoryScaleisusedto
tracktheirprogress.Onaverage,mostof
thepatientswhoaredepressedscore
around34-38(Severe).Afterthefirst
seriesofinfusionsarefinished(usually
overatwoweekperiod),thepatients'
scoresrangefrom0-6.Beck'sscalerange
from0-10forabout90daysafterthe
initialseries.Thescoresgradually
increaseandtherefore,maintenance
infusionsarerequiredevery90daysto
maintaindepressionrelief.
Beck'sDepressionInventory
Scale
5
WhatKetamineMeansForYour
Practice
OklahomaKetamineCenter
Acommonmisunderstandingwith
Ketamineclinicsisthesensethat
Ketaminereplacestheneedfora
healthcareprovider.Thiscouldnotbe
fartherfromthetruth.Thesepatients
arerequiredtomaketheirregular
appointmentsandoftenmustincrease
frequencyinordertobetestedfor
Ketaminemaintenance.Simplyadding
theBeck'sscaletoyourpatients'routine
appointmentisallthatisneeded.
Youdecidewhenthey
needtoreturnfor
their"boost"infusion
(typicallyonceevery
90days).
6
Anotherpopularmisconceptionisthe
notionthatKetaminewillinteractwith
currentprescribeddepression
medications.Ketamineinteractswith
theneurotransmitterGlutamateand
canbetakenalongwithanycurrent
FDAapproveddepressionmedications.
PatientswhoreceiveKetamineat
OklahomaKetamineCentercontinueto
takealloftheircurrentlyprescribed
medications.Itisuptoyoutodecide
whethertheycanbetakenoffany
medication.
Allpatientsundergoverystrict
guidelinespriortoKetaminetreatment.
Drugscreeningsandthorough
OklahomaKetamineCenter
Ketamineand
Prescription
Medications
7
OklahomaKetamineCenter
examinationofpatienthistoryis
required.Ketamineisnotforevery
patient.Theexclusioncriteriawill
disqualifypatientsintheprogram
suchasahistoryofuncontrolled
seizuresorhypertension.
Wetypicallyexpectpatientsto
haveexperiencedatleastoneortwo
FDAapproveddepressionmedications
withlittletonosuccessbeforebeing
referredtoourclinic.Nodepression
medicationshouldbestoppedwhileon
Ketaminetherapy(thedrug
Memantinecandecreasetheeffects
butisrarelyseenindepression
patients'medicationlists).
8
Ketamineisverysafeatlowdoses.
Patientswillbeeducatedonwhatto
expectduringtheirinfusions.The
patientswhofallasleepduringtheir
treatmentexperiencevividdreams.
Mostfindthisverypleasant(Notethat
theextremelylowdoseswillnotproduce
a"high"andassuchisnotaddictiveor
habitforming).Unlikemost
medications,Ketaminedoesnothaveto
be"tapered."Itcanbeinitiatedand
stoppedabruptlywithoutanyissues.
Patientstypicallyexperiencealittle
blurryvisionaftertheinfusionand
therefore,willrequiretohavesomeone
withthemtodrivethemhome.
OklahomaKetamineCenter
KetamineTreatment
9
Ifyoudecidetoreferpatientstoour
center,theymustsatisfyanextensive
checklisttoensuresafety.Ketaminehas
successfullytreatedallspectrumsof
depressionrangingfromPTSDto
schizophreniaalongwithsuicidal
ideation.
Yourpatientswillcometoour
centerunderyourorderstobe
monitoredbyouranesthesiaprovider
(TypicallyaDoctorofnurseAnesthesia
orCRNA).Vitalsignsaremonitored
every5minutesandincludeNIBP,
PulseOximeter,andEKG.
OklahomaKetamineCenter
KetamineTreatment
10
OklahomaKetamineCenter
Summary
1.)Ketamineisanoldanestheticdrug
withdrasticpositiveeffectsondepression
andanxiety
2.)Ketamineisanadjuncttoyour
currenttherapyandpatientsmust
continuetofollowupwithroutine
appointments
3.)Safetousealongwithanycurrent
FDAapproveddepressionmedicines
includingLithium
4.)Tremendouspatientsatisfactionas
illustratedbytheBeck'sInventoryScale
5.)Highlybackedbyrandomcontrol
trialsandpeerreviewedstudies
(abstractsincludedinthisbooklet)
11
OklahomaKetamineCenter
Summary
6.)Opensupnewavenuesforpatient
volume(ManyPCP'swanttosend
patientstoourcenterforKetamine
therapybutourcliniconlyaccepts
referralsbyalicensedhealthcare
provider.
12
OklahomaKetamineCenter
Abstract
Ketaminesafetyandtolerabilityin
clinicaltrialsfortreatment-resistant
depression
BenWanet.al.2015
OBJECTIVE:
Ketaminehasdemonstratedrapidantidepressant
effectsinpatientswithtreatment-resistant
depression(TRD);however,thesafetyand
tolerabilityofketamineinthispopulationhavenot
beenfullydescribed.Hereinwereportthelargest
studytodateofthesafety,tolerability,and
acceptabilityofketamineinTRD.
METHOD:
Datafrom205intravenous(IV)ketamineinfusions
(0.5mg/kgover40minutes)in97participantswith
DSM-IV-definedmajordepressivedisorder(MDD)
werepooledfrom3clinicaltrialsconductedbetween
2006and2012at2academicmedicalcenters.
Safetyandtolerabilitymeasuresincludedattrition,
adverseevents(AEs),hemodynamicchanges,and
assessmentsofpsychosisanddissociation.
RESULTS:Theoverallantidepressantresponse
rate,definedasa≥50%improvementin
Montgomery-AsbergDepressionRatingScalescore,
was67%(65of97participants).Fourof205
infusions(1.95%)werediscontinuedduetoAEs.
13
OklahomaKetamineCenter
Theoverallattritionratewas3.1%(3of97).Inthe
first4hoursaftertheinfusion,themostcommon
generalAEsweredrowsiness,dizziness,poor
coordination,blurredvision,andfeelingstrangeor
unreal.Approximatelyonethirdofindividuals
experiencedprotocol-definedhemodynamic
changes.Ketamineresultedinsmallbutsignificant
increasesinpsychotomimeticanddissociative
symptoms(allP<.05).Therewerenocasesof
persistentpsychotomimeticeffects,adversemedical
effects,orincreasedsubstanceuseinasubgroupof
patientswithavailablelong-termfollow-up
information.
CONCLUSIONS:
InthisrelativelylargegroupofpatientswithTRD,
ketaminewassafeandwelltolerated.
14
OklahomaKetamineCenter
Abstract
Mechanismsunderlyingdifferential
effectivenessofmemantineand
ketamineinrapidantidepressant
responses
Gideonset.al.2013
KetamineisanNMDAreceptor(NMDAR)
antagonistthatelicitsrapidantidepressant
responsesinpatientswithtreatment-resistant
depression.However,ketaminecanalsoproduce
psychotomimeticeffectsthatlimititsutilityasan
antidepressant,raisingthequestionofwhetherthe
clinicallytoleratedNMDARantagonistmemantine
possessesantidepressantproperties.Despiteits
similarpotencytoketamineasanNMDAR
antagonist,clinicaldatasuggestthatmemantine
doesnotexertrapidantidepressantactionsfor
reasonsthatarepoorlyunderstood.Inthisstudy,
werecapitulatetheketamineandmemantine
clinicalfindingsinmice,showingthatketamine,but
notmemantine,hasantidepressant-likeeffectsin
behavioralmodels.Usingelectrophysiologyin
culturedhippocampalneurons,weshowthat
ketamineandmemantineeffectivelyblockNMDAR-
mediatedminiatureexcitatorypostsynaptic
currentsintheabsenceofMg(2+).However,in
physiologicallevelsofextracellularMg(2+),we
identifiedkeyfunctionaldifferencesbetween
15
OklahomaKetamineCenter
ketamineandmemantineintheirabilitytoblock
NMDARfunctionatrest.Thisdifferentialeffectof
ketamineandmemantineextendstointracellular
signalingcoupledtoNMDARatrest,inthat
memantinedoesnotinhibitthephosphorylationof
eukaryoticelongationfactor2oraugment
subsequentexpressionofBDNF,whicharecritical
determinantsofketamine-mediatedantidepressant
efficacy.Theseresultsdemonstratesignificant
differencesbetweentheefficaciesofketamineand
memantineonNMDAR-mediated
neurotransmissionthathaveimpactson
downstreamintracellularsignaling,whichwe
hypothesizeisthetriggerforrapidantidepressant
responses.Thesedataprovideanovelframework
onthenecessaryfunctionalrequirementsof
NMDAR-mediatedneurotransmissionasacritical
determinantnecessarytoelicitrapid
antidepressantresponses.
16
OklahomaKetamineCenter
Abstract
Antidepressantefficacyofketaminein
treatment-resistantmajordepression:
atwo-siterandomizedcontrolledtrial.
Murroughet.al.2013
OBJECTIVE:
Ketamine,aglutamateN-methyl-d-aspartate
(NMDA)receptorantagonist,hasshownrapid
antidepressanteffects,butsmallstudygroupsand
inadequatecontrolconditionsinpriorstudieshave
precludedadefinitiveconclusion.Theauthors
evaluatedtherapidantidepressantefficacyof
ketamineinalargegroupofpatientswith
treatment-resistantmajordepression.
METHOD:
Thiswasatwo-site,parallel-arm,randomized
controlledtrialofasingleinfusionofketamine
comparedtoanactiveplacebocontrolcondition,the
anestheticmidazolam.Patientswithtreatment-
resistantmajordepressionexperiencingamajor
depressiveepisodewererandomlyassignedunder
double-blindconditionstoreceiveasingle
intravenousinfusionofketamineormidazolamina
2:1ratio(N=73).heprimaryoutcomewaschangein
depressionseverity24hoursafterdrug
administration,TasassessedbytheMontgomery-
ÅsbergDepressionRatingScale(MADRS).
17
OklahomaKetamineCenter
RESULTS:
Theketaminegrouphadgreaterimprovementin
theMADRSscorethanthemidazolamgroup24
hoursaftertreatment.Afteradjustmentfor
baselinescoresandsite,theMADRSscorewas
lowerintheketaminegroupthaninthemidazolam
groupby7.95points(95%confidenceinterval[CI],
3.20to12.71).Thelikelihoodofresponseat24
hourswasgreaterwithketaminethanwith
midazolam(oddsratio,2.18;95%CI,1.21to4.14),
withresponseratesof64%and28%,respectively.
CONCLUSIONS:
Ketaminedemonstratedrapidantidepressant
effectsinanoptimizedstudydesign,further
supportingNMDAreceptormodulationasanovel
mechanismforacceleratedimprovementinsevere
andchronicformsofdepression.Moreinformation
onresponsedurabilityandsafetyisrequiredbefore
implementationinclinicalpractice.
18
OklahomaKetamineCenter
KetamineandotherN-methyl-D-aspartate
receptorantagonistsinthetreatmentof
depression:aperspectivereview
Iadarolaet.al.2015
Currentpharmacotherapiesformajordepressive
disorder(MDD)andbipolardepression(BDep)have
adistinctlagofonsetthatcangenerategreat
distressandimpairmentinpatients.Furthermore,
asdemonstratedbyseveralreal-worldeffectiveness
trials,theirefficacyislimited.Allapproved
antidepressantmedicationsforMDDprimarilyact
throughmonoaminergicmechanisms,agonistsor
antagonistswithvaryingaffinitiesforserotonin,
norepinephrineanddopamine.Theglutamate
systemhasreceivedmuchattentioninrecentyears
asanavenuefordevelopingnoveltherapeutics.A
singlesubanestheticdoseinfusionofthe
noncompetitiveN-methyl-D-aspartate(NMDA)
receptorantagonistketaminehasbeenshownto
haverapidandpotentantidepressanteffectsin
treatment-resistantMDDandBDep..Inareverse
translationalframework,ketamine'sclinicalefficacy
hasinspiredmanypreclinicalstudiestoexplore
glutamatergicmechanismsofantidepressantaction.
Thesestudieshaverevealedenhancedsynaptic
plasticity/synaptogenesisvianumerousmolecular
andcellularmechanisms:releaseoflocal
translationalinhibitionofbrain-derivedneurotrophc
Abstract
19
factorandsecretionfromdendriticspines,
mammaliantargetofrapamycinactivationand
glycogensynthasekinase-3inhibition.Current
effortsarefocusedonextendingketamine's
antidepressantefficacy,uncoveringthe
neurobiologicalmechanismsresponsiblefor
ketamine'santidepressantactivityinbiologically
enrichedsubgroups,andidentifyingtreatment
responsebiomarkerstopersonalizeantidepressant
selection.OtherNMDAreceptorantagonistshave
beenstudiedbothpreclinicallyandclinically,which
haverevealedrelativelymodestantidepressant
effectscomparedwithketaminebutpotentially
otherfavorablecharacteristics,forexample,
decreaseddissociativeorpsychotomimeticeffects;
therefore,thereisgreatinterestindeveloping
novelglutamatergicantidepressantswithgreater
targetspecificityand/ordecreasedadverseeffects.
OklahomaKetamineCenter
20
OklahomaKetamineCenter
Abstract
AugmentationTherapyWithSerial
IntravenousKetamineOver18Months
inaPatientWithTreatmentResistant
Depression.
Hassamalet.al.2015
Majordepressivedisorderisasevereillnessthat
affects3%to7%ofadultsannuallyintheUnited
States.About30%oftheseindividualsarerefractory
tomultipletreatmenttrials.Recentreportshave
foundasignificantandalmostimmediate
improvementindepressivesymptomsaftersingleor
multipleketamineintravenousinfusions(IVIs)in
suchpatients.WepresentthecaseofA.B.,apatient
withtreatment-resistantdepression(TRD)including
tosubgenualdeepbrainstimulation,whowentinto
remissionafteraugmentationwith6ketamineIVIs
(0.5mg/kg)overa3-weekperiod.However,shehad
areemergenceofdepressivesymptoms4months
laterandreceivedasecondseriesof3ketamineIVIs
overthecourseofaweek.A.B.againwentinto
remissionandmaintainedthisforthenext8
months.Atthistime,sheexperiencedareemergence
ofdepressivesymptomsandwastreatedwiththe
thirdseriesofketamineIVIs(3infusionsoverthe
courseofaweek).
21
BecauseA.B.hasnowbeeninremissionfor6
months.A.B.hasreceivedatotalof12ketamine
IVIsoverthecourseof18months.Nosignificant
adverseeventshaveoccurred.Toourknowledge,
thisisthefirstcaseoflong-termketamineefficacy
asaugmentationtherapyinTRDoverthecourseof
18months.Thereisaneedforstudiesexamining
thelong-termmanagementofTRDwithIV
ketamine.Guidelinesformaintenanceketamine
IVIsinTRDalsoneedtobedeveloped.
OklahomaKetamineCenter
22
OklahomaKetamineCenter
Abstract
Arandomizedadd-ontrialofanN-
methyl-D-aspartateantagonistin
treatment-resistantbipolar
depression.
Diagranadoset.al.2010
CONTEXT:
Existingtherapiesforbipolardepressionhavea
considerablelagofonsetofaction.Pharmacological
strategiesthatproducerapidantidepressant
effects-forinstance,withinafewhoursordays-
wouldhaveanenormousimpactonpatientcareand
publichealth.
OBJECTIVE:
TodeterminewhetheranN-methyl-D-aspartate-
receptorantagonistproducesrapidantidepressant
effectsinsubjectswithbipolardepression.
DESIGN:
Arandomized,placebo-controlled,double-blind,
crossover,add-onstudyconductedfromOctober
2006toJune2009.
SETTING:
MoodDisordersResearchUnitattheNationalInstitute
ofMentalHealth,Bethesda,Maryland.Patients
EighteensubjectswithDSM-IVbipolardepression
(treatment-resistant).
23
OklahomaKetamineCenter
INTERVENTIONS:
Subjectsmaintainedattherapeuticlevelsoflithium
orvalproatereceivedanintravenousinfusionof
eitherketaminehydrochloride(0.5mg/kg)orplacebo
on2testdays2weeksapart.TheMontgomery-
AsbergDepressionRatingScalewasusedtorate
subjectsatbaselineandat40,80,110,and230
minutesandondays1,2,3,7,10,and14post
infusion.
MAINOUTCOMEMEASURES:
ChangeinMontgomery-AsbergDepressionRating
Scaleprimaryefficacymeasurescores.
RESULTS:
Within40minutes,depressivesymptoms
significantlyimprovedinsubjectsreceivingketamine
comparedwithplacebo(d=0.52,95%confidence
interval[CI],0.28-0.76);thisimprovementremained
significantthroughday3.Thedrugdifferenceeffect
sizewaslargestatday2(d=0.80,95%CI,
0.55-1.04).Seventy-onepercentofsubjectsresponded
toketamineand6%respondedtoplaceboatsome
pointduringthetrial.Onesubjectreceiving
ketamineand1receivingplacebodevelopedmanic
symptoms.Ketaminewasgenerallywelltolerated;
themostcommonadverseeffectwasdissociative
symptoms,onlyatthe40-minutepoint.
CONCLUSION:
Inpatientswithtreatment-resistantbipolar
depression,robustandrapidantidepressanteffects
resultedfromasingleintravenousdoseofanN-
methyl-D-aspartateantagonist.
Contact:
Phone#:405-471-5670
Fax#:405-471-5671
Address:2916AstoriaWay
Suite150
Edmond,OK73034
Website
www.oklahomaketaminecenter.com
Hours:
Mon: 8am-4pm
Tue: 8am-4pm
Wed: 8am-4pm
Thu: 8am-4pm
Fri: 8am-4pm
Sat:closed
Sun:closed
ContactUs:
Phone#:405-471-5670
Fax#:405-471-5671
Address:2916AstoriaWay
Suite150
Edmond,OK73034
Ketamine
for
Depression
ReferenceGuideforHealth
Professionals