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