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Neuros-mula-oninTreatmentResistant

DepressionHoracioACapote,MD,FAPA,FASAM

DirectoroftheNeuropsychiatryDivisionDentNeurologicIns-tute

Witheachsuccessivetreatmentfailure,thelandscapechanges:

MajorDepressionCurrentTreatmentLandscape

Trivedi(2006)AmJPsychiatry;Rush(2006)AmJPsychiatry;Fava(2006)AmJPsychiatry;McGrath(2006)AmJPsychiatry

High

Low

AdverseEvents

Long-TermDurability

Efficacy

Responsive ResistantTreatmentEffec-veness

Likelihoodoflong-termdurabilityofbenefitdeclines

Intoleranceduetoadverseeventsworsens

Likelihoodofbenefitfromthenextop?ondiminishes

OUTC

OME

2

UnmetMedicalNeeds

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STAR*DStudydemonstratesthatcurrenttreatmenthaslimitedeffec-veness

Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry 3

UnmetMedicalNeeds

Likelihoodofdiscon-nuingtreatmentincreaseswitheachnewmedica-ona\empt

SystemicDrugSideEffects

q  WeightGain

q  Cons-pa-on

q  Diarrhea

q  Nausea

q  Drowsiness

q  Insomnia

q  DecreasedLibido

q  NervousAnxiety

q  IncreasedAppe-te

q  DecreasedAppe-te

q  Fa-gue

q  Headache/Migraine

q  AbnormalEjacula-on

q  Impotence

q  Swea-ng

q  Tremor

q  TreatmentDiscon-nua-onSideEffects

q  Weakness

q  DryMouth

q  Dizziness

Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry; Neuronetics, Inc. (data on file)

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UnmetMedicalNeeds

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TRDattheDNI

VNS

TMS

DBS

Ketamine(IV)

ECT

VagalNerveS-mula-on

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The VNS Therapy System Components

1.GeorgeMS,etal.CNSSpectr.2000;5(11):43-52.2.HardenCL,etal.EpilepsyBehav.2000;1:93-99.3.Ben-MenachemE,etal.EpilepsyRes.1995;20:221-227.4.KrahlSE,etal.Epilepsia.1998;39:709-714.5.WalkerBR,etal.Epilepsia.1999;40:1051-1057.6.KrahlSE,etal.JPsychiatrRes.2004;38:237-240.

Ra-onaleforVNSTherapyindepression

•  Anatomicalprojec?onsofvagusnerveintoareasofthebrainknowntobeimplicatedindepression1

•  Evidenceofmoodimprovementinepilepsystudies,irrespec?veofseizurecontrol2

•  Useofan?convulsantsasmoodstabilizers/augmenta?onhasestablishedhistoryinpsychiatry1

•  NeuroimagingdatahavedemonstratedthatVNSTherapyaffectsmanyareasofthebrainimplicatedinneuropsychiatricdisorders1

•  EffectsonneurotransmiMersimplicatedindepression1,3-6•  Ac?vityinanimalan?depressantmodel(FST)

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PivotalStudyLong-TermAnalysesDemonstrateResponseRatesIncreaseOverTimeDuring

Adjunc-veVNSTherapy

0

5

10

15

20

25

30

35

IDS-SR HRSD24

%Respo

nse

14

1819

22

27

1517

23

3033

1720

27

32

MADRS

EvaluableObserved

Responsedefinedas≥50%reduc-oninIDS-SR30,HRSD24,MADRScomparedwithbaseline

3Months(n=203-205)

6Months(n=192-197)

9Months(n=184-186)

12Months(n=180-181)

24Months(n=157)

RushAJ,etal.BiolPsychiatry.2005;58:355-363.24-monthDataonFile,Cyberonics,Inc.

fMRI=func-onalmagne-cresonanceimaging.DatafromtheMedicalUniversityofSouthCarolinaCenterforAdvancedImagingResearch.

fMRIShowsIncreasedLimbicAc-vityinBrainsofPa-entsWithTRDDuringVNSTherapy

RightInsulaOrbitofrontalCortex

Mid-CingulateGyrus

R L

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TranscranialMagne-cS-mula-on

TMS:SylvanusP.Thompson(1910)LondonA.T.Barker,etall(1985)Sheffield

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BestPrac-cesTreatmentGuidelineforDepression

Basedon2010APAguidelinesand

Adapted from: Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd Edition, APA (2010)

UnmetMedicalNeeds

Trea-ngtheBrainasanElectrochemicalTarget

Majorbrainregionsknowntobeinvolvedinmoodregula5on

Amygdala

VentromedialPrefrontalCortex

PrefrontalCortex

AnteriorCingulateGyrus

Brainac-vitycanbealtered:•  Chemically(eg,viadrugs)

or,•  Electrically(eg,viaTMS)

–  Drugac?onisanatomicallydiffuseandsystemic

–  TMSisfocused,non-invasiveandnon-systemic

Pizzigalli (2011) Neuropsychopharmacology

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TranscranialMagne-cS-mula-on(TMS)

l ThetreatmentcoilproducesMRI-strengthmagne?cfieldpulses.

l Magne?cfieldpulsespassunimpededthroughthecraniumfor2-3cm.andinduceasmallelectriccurrent.

l  Inducedelectriccurrentss?mulatethefiringofnearbyneurons,causingthereleaseofneurotransmiMersandclinicaleffects.

Faraday (1839) Experimental Research in Electricity. Vol 1; Barker (1991) J Clin Neurophysiol; Barker (1985) Lancet

Ac-va-onoffronto-cingulatebraincircuitfollowingacourseofTMSappliedtotheleldorsolateralprefrontalcortexinpa-entswithMajorDepression

TargetedEffectsonMoodCircuitsinBrain

Kito (2008) J Neuropsychiatry Clin Neurosci

TMSCoilL

L

R

R

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DeepBrainS-mula-on

NeuroanatomyofDepression

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Ra-onaleforTarge-ngtheVentralCapsule/VentralStriatum

1.  VSisacentralnodeinthelimbic-cor-cal-subcor-calnetworkthoughttobeinvolvedinemo-onalprocessing

2.  VSiscentralinprocessingrewardandpleasureinforma-on

3.  VSisideallysuitedtomodulatereward-mo-vatedbehavior

4.  VCcontainswhitema\ertractsconnec-ngVStoareasmen-onedabove

ElectrodePlacement

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Opera-veResultsandPost-opManagement

•  Immediatefeelingofa“smile”or“giggle”whens-mulatorturnedon

•  Increaseinsubjec-vemoodimmediately,decreaseinanxiety–  Describedpa\ernofbothshorttermandlongternchangesleadingtoimprovement

•  Con-nuedonhomemedica-ons,recoveryperiod,dischargedonPOD3

IntravenousKetamine

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Ketamine

ResponseRatestoKetamineinaDouble-BlindPlaceboCrossoverTrialinPa-entswithTreatment-ResistantMajor

Depression(N=18)

0102030405060708090100

13%

35%

53%56%

71%

58%53%

Venlafaxine SSRIKetamine Bupropion

Response:50%decreaseinHAMDfrombaseline

35%

Placebo

**Thaseetal.JClinPsychiatry2005;66:974-81

***62-65%

HistoricalControl

Zarateetal.ArchGenPsychiatry2006;63:856-64.

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Rela-veabundanceofneurotransmi\ers

•  Glutamate~60%ofsynapses

•  GABA~30%ofsynapses

•  Monoamines,pep-des,otherAAs(e.g.glycine)<5%

GlutamatePharmacology•  Glutamateisoneofthemostcommontransmi\ersintheCNS–  Fast,excitatorytransmi\er;receptorsonalmostallneurons.Transmi\erin~60%ofneurons,espcortex,limbicstructures.

•  Glutamatebindsto4classesofreceptor–  three"ionotropic"receptorclasses-ligand-gatedionchannelswhicharecharacterizedbythedifferentligandsthatbindtothem:

•  AMPA•  kainicacid•  N-methyl-D-aspartateorNMDA

–  oneG-proteincoupledor"metabotropic"receptorclass.

H2N

COOH COOH

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GlutamateFunc-on•  Underphysiologicalcondi-ons,ac-va-onofionotropic

receptorsinneuronsini-atestransientdepolariza-onandexcita-on.

•  AMPA-Rsmediatethefastcomponentofexcitatorypostsynap-ccurrents

•  NMDA-Rsunderlieaslowercomponent.•  AMPA-RsmodulateCa++influxthruNMDA-Rs.

–  Depolariza-onofthepostsynap-cneuronalmembraneviaAMPA-RsrelievestheMg++blockoftheNMDA-Rionchannel(thisoccursinNMDA-Runderres-ngcondi-ons).ThisallowscontrolledCa++influxthroughtheNMDA-R.Thisvoltage-dependentmodula-onoftheNMDA-Rresultsinac-vity-drivensynap-cmodula-on.

•  Glutamateoverac-vitycanleadtoneuronaldeathduetoCa++toxicity,otherassociatedmechanisms.

H2N

COOH COOH

NMDA-ReceptorsStructure-tetramersoftwoNR1subunitsandtwoNR2

subunits(somebrainareashaveNR3subunits).Bindingsitesontheextracellulardomain:NR1:co-agonist

glycine;NR2:glutamate.Forefficientionchannelopening,theNMDAreceptorrequiresbothglutamateandtheco-agonistglycine.

Bindingsitesintheionchannel:Mg2+;PCP/ketaminesiteNMDAantagonists:Synthe-cantagonistsinclude:

MK-801(dizocilpine)PhencyclidineKetamineDextromethorphanMeman-ne,AmantadineProcyclidine

NMDAmodulators:Mg2+blockstheNMDAchannelinavoltage-dependentmanner.-Na+,K+andCa2+notonlypassthroughtheNMDAreceptorchannelbutalsomodulatetheac-vityofNMDAreceptors.

Ketamine and

- Zn2+ blocks the NMDA current in a non-competitive and voltage-independent manner. - The activity of NMDA receptors is also sensitive to the changes in H+ concentration, and is partially inhibited by the ambient concentration of H+ under physiological conditions.

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80

60

40

20

0 40 80 110 230 1 2 3 7 10 14

Minutes Days Time after infusion

MADR

S Re

spon

ders

(%)

Ketamine Placebo

40 80 110 230 1 2 3 7 10 14

Minutes Days Time after infusion

40

30

20

10

0

MADR

S sc

ore

Ketamine Placebo

Single Dose Ketamine Infusion Studies (1)

• Diazgranados; Arch Gen Psych 2010

• Treatment refractory bipolar depression, unmedicated

• Randomized, double blind, 2 period crossover

• Ketamine (0.5mg/kg) or placebo via 40 minute IV

infusions

• Assessments to 14 days

100

90

80

70

60 (%)

50

40

30

20

10

0

100

90

80

70

60 (%) 50

40

30

20

10

0

40 80 110 230 24 48 72 168 - - - - -mins- - - - - - - - - - - - - -hours- - - - - - (time)

40 80 110 230 24 48 72 168 - - - - -mins- - - - - - - - - - - - - -hours- - - - - - (time)

Ketamine Placebo

Percent of responders (>50% ↓HAMD) Percent in remission (HAMD <7)

• Main side effects of ketamine: Perceptual disturbances and dizziness; confusion; elevated blood pressure; euphoria; increased libido

• Generally occurred in 1st 20min of infusion.

•  Zarate,ArchGenPsych2006•  TreatmentresistantMDD,unmedicated•  Single0.5mg/kgIVinfusion;placebocontrolled,crossoverdesign

SingleDoseKetamineInfusionStudies(2)

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ElectroConvulsiveTherapy

•  Early(Pre-ECT)History•  Inthe1933Dr.ManfredSakel

developedInsulinComaTherapy(Insulin-shockbehandlung)–treatedopioiddependentpt’sfirst,laterschizophrenia.• Txswereoccasionally,butnotalways,accompaniedbyseizures.• Sakellaterclaimedtohaveinventedconvulsivetherapy,butthisisdisputed.

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HistoryofConvulsiveTherapies•  1938–UgoCerlexandLucioBiniinduceseizuresinRomeusingelectricals-muli

•  1940–RenatoAlmansiandDavidImpastoadministerECTatColumbusHospitalinNYC.LotharKalinowskystartsgivingECTatPsychiatricIns-tute

•  1940-A.E.Benne\usescurareformusclerelaxa-onwithMetrazolconvulsivetherapy

•  1952–HolmbergusessuccinylcholineasamusclerelaxantwithECT

(Image provided courtesy of Renato Sabattini, PhD)

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(Reproduced with permission from: Somatics, LLC)

Thymatron™ System IV - Integrated ECT Instrument

ElectricalS-mulus

•  Brief-pulsesquare-waveAC•  Voltageapprox.200V(basedupon220Ωimpedance)•  Current0.9A•  Frequency30-70Hz•  Pulsewidth0.5-2msec•  Dura-on0.1-8sec•  Charge25-504mC(5-99J)

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Howdoesitwork?•  Seizure-15to180sec(byEEG)•  Low-doseRULECT-Lesseffec-veclinicallydespiteadequateseizuredura-on

•  Down-regula-onofbetareceptors•  Up-regula-onof5HT2receptors•  GABA(an--convulsanttheoryofECT)•  BDNF(reversalofhippocampalatrophy)

An-convulsanttheoryofECT

•  IncreasingseizurethresholdduringacourseofECTisassociatedwithclinicalresponse

•  Hypothesis:linkedan-convulsantandan-depressantresponsetoECT

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ECTinducedseizure

•  Dischargeofneuronalpopula-onwhichis:– Paroxysmal– Synchronous– Repe--ve

•  Post-ictalsuppressionfollowsseizure–  Inhibitoryinterneurons– GABA(asdetectedbyMRS)

ECS(ECT)induceddepolariza-onNE,5HTcAMPPKACREBBDNF

DumanRSandVaidyaVA.JECT,14(3):181-193,1998.

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Modern(Modified)ECT

•  Generalanesthesia(propofol1mg/kg,etomidate0.15mg/kg,methohexital1mg/kg))

•  Musclerelaxant(succinylcholine1mg/kg,mivacurium0.15mg/kg))

•  An-cholinergic(glycopyrrolate0.2mg,atropine0.4mg)

•  Oxygen/ven-la-onbymask•  Con-nuouscardiacandEEGmonitoring•  (Otherpre-andpost-medica-onsasindicated–NTG,Beta-blockers,promethazine,ketorolac,midazolam,sumatriptan,sodiumamytal)

Diagnos-cIndica-ons

•  MDD•  BPAD•  Psychosis(Schizophrenia,SAFD)•  Catatonia•  NMS•  PD•  Delirium

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ReasonstoconsiderECTfirst

•  Severesucidality•  Catatonia/NMS•  Pa-entpreference(usuallypreviousECT)•  Pregnancyandseverepsychiatricillness

AllModali-esAreNeeded

•  Dent:theonlysiteinNorthAmericawithallTx’s

•  Therewillalwaysbenoneresponders

•  Avoidsusingonlyonetreatmentforall

•  Ourpa-entsdeservethebesttreatments

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ThankYou

Ques-ons?