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Brain Stimulation Brain Stimulation Therapies for Therapies for
Treatment Resistant Treatment Resistant DepressionDepressionJohn P. O’Reardon, MDJohn P. O’Reardon, MD
Associate Professor,Associate Professor,Department of PsychiatryDepartment of Psychiatry
Director, TMS Laboratory and Director, TMS Laboratory and Treatment Resistant Depression Treatment Resistant Depression
ClinicClinic
University of PennsylvaniaUniversity of Pennsylvania
DisclosuresDisclosuresConsultant:Consultant: NoneNone
Full-time Employee:Full-time Employee: NoneNone
Grant/Research Grant/Research Support:Support:
Bristol Myers Squibb, Cyberonics, Bristol Myers Squibb, Cyberonics, Neuronetics, Pfizer Neuronetics, Pfizer
Speakers' Bureau/Speakers' Bureau/Lecture Honoraria:Lecture Honoraria:
Bristol Myers Squibb, Lilly Bristol Myers Squibb, Lilly Pharmaceuticals Pharmaceuticals
Major Stockholder:Major Stockholder: NoneNone
Other Financial/Other Financial/Material Interest:Material Interest:
NoneNone
Pre-Lecture ExamPre-Lecture ExamQuestion 1Question 1
Magnetic Seizure Therapy (MST) differs from Magnetic Seizure Therapy (MST) differs from ECT in that:ECT in that:
a.a. the goal is not to induce a therapeutic seizurethe goal is not to induce a therapeutic seizure
b.b. the use of focused stimulation to produce a the use of focused stimulation to produce a seizureseizure
c.c. general anesthesia is not requiredgeneral anesthesia is not required
d.d. daily sessions of MST are needed to produce daily sessions of MST are needed to produce a therapeutic effecta therapeutic effect
e.e. it has a more benign profile in terms of it has a more benign profile in terms of cognitive adverse effectscognitive adverse effects
Question 2Question 2The most common side effect reports The most common side effect reports
with VNS is:with VNS is:
a.a. weight gainweight gain
b.b. sexual dysfunctionsexual dysfunction
c.c. cognitive impairmentcognitive impairment
d.d. hoarsenesshoarseness
e.e. chest painchest pain
Question 3Question 3Deep brain stimulation is currently FDA Deep brain stimulation is currently FDA
approved for the treatment of:approved for the treatment of:
a.a. auditory hallucinations in auditory hallucinations in schizophreniaschizophrenia
b.b. chronic neuropathic painchronic neuropathic pain
c.c. obsessive compulsive disorderobsessive compulsive disorder
d.d. parkinson’s Diseaseparkinson’s Disease
e.e. intractable migraineintractable migraine
Question 4Question 4Transcranial Magnetic Stimulation (TMS) Transcranial Magnetic Stimulation (TMS)
differs from Magnetic Resonance differs from Magnetic Resonance Imaging (MRI) technology in that:Imaging (MRI) technology in that:
a.a. the magnetic fields produced are much the magnetic fields produced are much weaker in intensityweaker in intensity
b.b. the rate of change of the magnetic field the rate of change of the magnetic field is higher with an MRI versus TMSis higher with an MRI versus TMS
c.c. MRI technology activates neurons MRI technology activates neurons whereas TMS does notwhereas TMS does not
d.d. scalp discomfort is common with TMS scalp discomfort is common with TMS but not with an MRIbut not with an MRI
Question 5Question 5Which of the following statements about ECT Which of the following statements about ECT
is not true?is not true?a.a. ECT appears to be particularly efficacious ECT appears to be particularly efficacious
in psychotic depressionin psychotic depressionb.b. ECT is not effective in the treatment of ECT is not effective in the treatment of
maniamaniac.c. ECT is effective in the treatment of bipolar ECT is effective in the treatment of bipolar
depressiondepressiond.d. ECT is associate with retrograde memory ECT is associate with retrograde memory
impairmentsimpairmentse.e. ECT is effective in the treatment of ECT is effective in the treatment of
pharmacotherapy-resistant major pharmacotherapy-resistant major depressiondepression
Educational GoalsEducational Goals Describe the range of brain stimulation Describe the range of brain stimulation
technologies (TMS, VNS, DBS, & DCS) technologies (TMS, VNS, DBS, & DCS) being currently investigated in psychiatry being currently investigated in psychiatry for possible therapeutic applicationfor possible therapeutic application
Examine current evidence for application Examine current evidence for application of these devices in a number of clinical of these devices in a number of clinical disordersdisorders
Understand the comparative safety profile Understand the comparative safety profile and adverse events associated with these and adverse events associated with these device technologies for brain stimulationdevice technologies for brain stimulation
OverviewOverview Neurotherapeutics - DefinitionsNeurotherapeutics - Definitions
Electroconvulsive Therapy (ECT)Electroconvulsive Therapy (ECT)
Transcranial Magnetic Stimulation Transcranial Magnetic Stimulation (TMS)(TMS)
Magnetic Seizure Therapy (MST)Magnetic Seizure Therapy (MST)
Vagus Nerve Stimulation (VNS)Vagus Nerve Stimulation (VNS)
Deep Brain Stimulation (DBS)Deep Brain Stimulation (DBS)
DefinitionsDefinitionsNeurotherapeuticsNeurotherapeutics
Treatments for nervous system disorders Treatments for nervous system disorders Pharmacological and other modalitiesPharmacological and other modalities
NeuromodulationNeuromodulationTherapeutic alteration of nerve activityTherapeutic alteration of nerve activityCentral, peripheral or autonomic nervous Central, peripheral or autonomic nervous systemssystemsElectrically or pharmacologicallyElectrically or pharmacologicallyImplanted devicesImplanted devicesPain, movement disorders, spasticity, Pain, movement disorders, spasticity, epilepsy, sensory deprivation, urinary epilepsy, sensory deprivation, urinary incontinence, gastric dysfunction, incontinence, gastric dysfunction, pancreatitis/visceral disorderspancreatitis/visceral disorders
NeurostimulationNeurostimulation Typically refers to implantable devices with power source, Typically refers to implantable devices with power source, lead wires, electrodes and programming componentslead wires, electrodes and programming components
Electroconvulsive Electroconvulsive Therapy (ECT)Therapy (ECT) 11stst administered in 1938 (in administered in 1938 (in
Rome)Rome) FDA - approvedFDA - approved
since 1979 (grand-fathered)since 1979 (grand-fathered) Brief electrical pulse passed Brief electrical pulse passed
through scalp (0.5 to 6 through scalp (0.5 to 6 seconds duration)seconds duration)
Patient under anesthesiaPatient under anesthesia Produces seizure on EEGProduces seizure on EEG Muscle paralysis prevents Muscle paralysis prevents
convulsive movementconvulsive movement Bilateral or unilateralBilateral or unilateral 6 - 12 treatments6 - 12 treatments 2 - 3 treatments per week2 - 3 treatments per week
Efficacy of ECT versus Efficacy of ECT versus Sham controlSham control
UK ECT Review Group, Lancet 2003; 361: 799-808
Trial # of Participants Standard Effect Size (95%CI)Trial # of Participants Standard Effect Size (95%CI)
Wilson 1963 12 -1.078 (-2.289 to 0.133)Wilson 1963 12 -1.078 (-2.289 to 0.133)
West 1981West 1981 25 25 -1.255 (-2.170 to -0.341) -1.255 (-2.170 to -0.341)
Lambourn 1978 40Lambourn 1978 40 -0.170 (-0.940 to 0.600) -0.170 (-0.940 to 0.600)
Freeman 1978 40Freeman 1978 40 -0.629 (-1.264 to 0.006) -0.629 (-1.264 to 0.006)
Gregory 1985 69Gregory 1985 69 -1.418 (-2.012 to -0.824) -1.418 (-2.012 to -0.824)
Johnstone 1980 70Johnstone 1980 70 -0.739 (-1.253 to -0.224) -0.739 (-1.253 to -0.224)
Pooled Fixed EffectsPooled Fixed Effects -0.911 (-1.180 to -0.645) -0.911 (-1.180 to -0.645)
Pooled Random EffectsPooled Random Effects -0.908 (-1.270 to -0.537) -0.908 (-1.270 to -0.537)
1 103 2
Favors ECT FavorsSham
Trial* # of Participants Standard Effect Size (95%CI)Trial* # of Participants Standard Effect Size (95%CI)
Steiner 1978 Steiner 1978 12 0.369 (-0.840 to 1.578)12 0.369 (-0.840 to 1.578)
Wilson 1963Wilson 1963 1212 -0.513 (-1.663 to 0.637) -0.513 (-1.663 to 0.637)
Davidson 1978 Davidson 1978 1919 -1.389 (-2.449 to -0.328) -1.389 (-2.449 to -0.328)
McDonald 1966 22McDonald 1966 22 -0.930 (-1.813 to -0.047) -0.930 (-1.813 to -0.047)
Gangadhar 1982 Gangadhar 1982 3232 1.287 (0.406 to 2.169) 1.287 (0.406 to 2.169)
MacSweeney 1975MacSweeney 1975 2727 -0.714 (-1.492 to 0.065) -0.714 (-1.492 to 0.065)
Dinan 1989Dinan 1989 3030 -0.196 (-0.926 to 0.534) -0.196 (-0.926 to 0.534)
Janakiramaiah 2000Janakiramaiah 2000 3030 -1.095 (-1.863 to -0.328) -1.095 (-1.863 to -0.328)
Folkerts 1997Folkerts 1997 4040 -1.336 (-2.032 to -0.640) -1.336 (-2.032 to -0.640)
Herrington 1974Herrington 1974 4343 -1.497 (-2.174 to -0.821) -1.497 (-2.174 to -0.821)
Stanley 1962Stanley 1962 4747 -1.342 (-2.047 to -0.638) -1.342 (-2.047 to -0.638)
MRC 1965MRC 1965 204204 -0.559 (-0.883 to -0.234) -0.559 (-0.883 to -0.234)Greenblatt 1964Greenblatt 1964 242242 -1.683 (-2.020 to -1.346) -1.683 (-2.020 to -1.346)
Other trials are not included: Kendrick 1965, Bruce 1960, Bagadia 1981, Hutchinson 1963, Robin 1962
Pooled Fixed Effects -1.010 (-1.170 to -0.856)
Pooled Random Effects -0.802 (-1.290 to -0.289)
Efficacy ECT versus Efficacy ECT versus AntidepressantsAntidepressants
UK ECT Review Group, Lancet 2003; 361: 799-808
-3 1 0 1
Favors PT
3
Favors ECT
ECT LimitationsECT LimitationsLimitationsLimitations
Headache, muscle achesHeadache, muscle aches
Cognitive Side Effects: MemoryCognitive Side Effects: Memory
Access: Hospital, Often InpatientAccess: Hospital, Often Inpatient
StigmaStigma
Anesthesia RisksAnesthesia Risks
CostCost
Maintenance: ECT v. medsMaintenance: ECT v. meds
Role of ECT in 21st century
ECT remains a gold standard treatment ECT remains a gold standard treatment for severe depression and has yet to be for severe depression and has yet to be superseded by medication or by any superseded by medication or by any other brain stimulation treatmentother brain stimulation treatment
In recent multicenter trials remission In recent multicenter trials remission rates with ECT are about 75%rates with ECT are about 75%
This is 3-4 fold superior to This is 3-4 fold superior to antidepressantsantidepressants
Clinical indications Clinical indications for ECTfor ECT
Unipolar and Bipolar DepressionUnipolar and Bipolar Depression
Catatonia (due to schizophrenia, mood Catatonia (due to schizophrenia, mood disorders, or medical disorders)disorders, or medical disorders)
Mania non-responsive to medicationMania non-responsive to medication
Occasionally - schizoaffective disorder, Occasionally - schizoaffective disorder, NMS, PD, severe depression in pregnancyNMS, PD, severe depression in pregnancy
Transcranial Magnetic Transcranial Magnetic Stimulation (TMS)Stimulation (TMS)Non-invasiveNon-invasive technologytechnology
USA: Investigational USA: Investigational
Approved: Canada, Israel, EuropeApproved: Canada, Israel, Europe
Strong, pulsed (e.g., 2/28 sec) Strong, pulsed (e.g., 2/28 sec) magnetic fields pass through magnetic fields pass through skull unimpededskull unimpeded
Coil placed on head in awake Coil placed on head in awake patientpatient
Induces electrical current in Induces electrical current in cortex which depolarizes neuronscortex which depolarizes neurons
Greater control over site and Greater control over site and intensity of stimulation (e.g, left intensity of stimulation (e.g, left DLPFC)DLPFC)
No anesthesia, no cognitive No anesthesia, no cognitive adverse effectsadverse effects
This information concerns a use that has not been approved by the U.S. Food and Drug Administration
How do MRI and TMS How do MRI and TMS Differ?Differ?
MRIMRI TMSTMSMagnetic Field Magnetic Field StrengthStrength
1.5 Tesla1.5 Tesla 2 Tesla2 Tesla
Rate of Change Rate of Change of Magnetic of Magnetic FieldField
20 T/s20 T/s 20,000 20,000 T/sT/s
Induces Current Induces Current in Brainin Brain
NoNo YesYes
Overview of TMS1) Electrical energy in insulated coil on the scalp induces2) Pulsed magnetic field of about 1.5 Tesla in strength3) Passes unimpeded through thecranium for 2-3 cm4) In turn induces a focal electrical current in the brain5) Get desired local and distal effects on the target neural circuitry6) Delivered as single pulses or repeated trains (rTMS)
TMS application in TMS application in PsychiatryPsychiatry
Best studied in depression, with about Best studied in depression, with about 30 RCT of active versus sham TMS 30 RCT of active versus sham TMS (n=1500)(n=1500)
Evidence for efficacy reasonable at this Evidence for efficacy reasonable at this juncture with an effect size of about juncture with an effect size of about 0.75 in most recent metanalysis0.75 in most recent metanalysis11
Safety is excellent, with minimal side Safety is excellent, with minimal side effects, & low dropout rates (~ 5%)effects, & low dropout rates (~ 5%)22
1. Gross et al. Acta Psy Scan 2007. 2. O’Reardon et al. Bio Psy 2007
Multicenter study of TMS Multicenter study of TMS in MDDin MDD
Lead-InMed free7-10 days
Acute Treatment PhaseMedication free
Taper Phase3 weeks
Active TMS (N=155)• 120% MT• 10Hz• 4 sec on-time/26 sec off-time• 3000 pulses/session• Sessions 5 days/week
Sham TMS (N=146)• <3% field exposure at cortex
Primary Efficacy @ 4 weeks
Secondary Efficacy @ 6 weeks
Acute durability of Effect @ 9 weeks
6 sessions (active)
6 sessions (sham)
O’Reardon et al., Biological Psychiatry, 2007
0
5
10
15
20
25
Week 2 Week 4 Week 6
Rat
e (%
)
* P < .05 vs. sham, ** P < .01 vs. sham, LOCF analysis
Response Rates
*
**
Categorical Outcomes at 4 & 6 weeks
= Active Responders = Sham Responders = Active Remitters = Sham Remitters
Remission Rates
0
2
4
6
8
10
12
14
16
Week 2 Week 4 Week 6
*
TMS for other TMS for other disordersdisorders TMS has an inbuilt flexibility in treatment TMS has an inbuilt flexibility in treatment
targetingtargeting
Electromagnet can be moved over scalp Electromagnet can be moved over scalp and targeted to desired area of the cortexand targeted to desired area of the cortex
Frequency selection allows activation or Frequency selection allows activation or inhibition of circuits accessible at the inhibition of circuits accessible at the level of cortex, guided by imaging level of cortex, guided by imaging findingsfindings
Other possible applications Other possible applications of TMSof TMS Auditory hallucinations in schizophrenia –
1 Hz TMS over superior temporal gyrus
PTSD – 10 Hz over R prefrontal cortex
ADHD – to target the R medial frontal gyrus
Other areas being studied include stroke rehab, migraine, Tourette’s Syndrome
Schizophrenia and Schizophrenia and TMSTMS
Application of continuous 1 Hz TMS over Application of continuous 1 Hz TMS over temperoparietal cortex to inhibit generation temperoparietal cortex to inhibit generation of AH of AH
Recent metaanalysis of 10 controlled studies Recent metaanalysis of 10 controlled studies (n=212) was positive, with a substantial ES (n=212) was positive, with a substantial ES of 0.76 (95% CI range 0.36-1.17)of 0.76 (95% CI range 0.36-1.17)
Sample sizes generally small (range 10-50 Sample sizes generally small (range 10-50 subjects)subjects)
Well tolerated, implies language perceptual Well tolerated, implies language perceptual disturbance key to etiology of AHdisturbance key to etiology of AH
Aleman et al. J Clin Psy 2007;68:416-21
Post-operative pain & Post-operative pain & TMSTMS
Recent sham-controlled study of 1 session Recent sham-controlled study of 1 session of 20 minutes of 10 Hz TMS over L PFC of 20 minutes of 10 Hz TMS over L PFC (4000 pulses total) in bariatric surgery (4000 pulses total) in bariatric surgery patients (n=20)patients (n=20)
Main outcome was PCA of morphine/opioids Main outcome was PCA of morphine/opioids in first 48 hours post surgeryin first 48 hours post surgery
With active TMS there was 40% less usage With active TMS there was 40% less usage of PCA (=24 mg less of morphine over 48 of PCA (=24 mg less of morphine over 48 hours) hours)
Bockardt et al. ACNP 2006
TMS in MigraineTMS in Migraine TMS used to understand the pathophysiology of TMS used to understand the pathophysiology of
migraine – migraineurs have been shown to a migraine – migraineurs have been shown to a lower phosphene threshold (excitation) over V1 lower phosphene threshold (excitation) over V1 (primary visual cortex) compared to controls(primary visual cortex) compared to controls
Recent positive results with inhibitory TMS in Recent positive results with inhibitory TMS in controlled study of migraine with occipital targetcontrolled study of migraine with occipital target
A 2:1 advantage found over the control condition A 2:1 advantage found over the control condition in migraine with aura (~75% vs. 40%) in migraine with aura (~75% vs. 40%)
A TMS Investigational Device for Migraine relief
Lightweight device, intended for home use, delivers fixed pulse, has over use limits in place
TMS future as clinical TMS future as clinical treatmenttreatment
Currently FDA reviewing application for Currently FDA reviewing application for approval for TMS as a treatment for major approval for TMS as a treatment for major depressiondepression
TMS clinically available in Canada, Australia, TMS clinically available in Canada, Australia, Israel & EuropeIsrael & Europe
Available off-label in some centers in the USAvailable off-label in some centers in the US
TMS is a safe intervention & may be promising TMS is a safe intervention & may be promising option for a number of psychiatric & option for a number of psychiatric & neurological disordersneurological disorders
Magnetic Seizure Magnetic Seizure Therapy (MST)Therapy (MST)
InvestigationalInvestigational
Magnet-induced stimulus (like Magnet-induced stimulus (like rTMS)rTMS)
High Intensity High Intensity
Target “antidepressant regions”Target “antidepressant regions”
Fewer side effectsFewer side effects
3 sessions/week3 sessions/week
Same as ECTSame as ECTAnesthesiaAnesthesia
Tonic clonic seizureTonic clonic seizure
Monitor EEG, vitalsMonitor EEG, vitals
This information concerns a use that has not been approved by the U.S. Food and Drug Administration
MST: Shorter Period of Post-MST: Shorter Period of Post-Ictal Disorientation and Ictal Disorientation and
InattentionInattention
Med
ian
Tim
e (m
in)
to R
eco
ver
Fu
ll O
rien
tati
on
*Threshold MST v.ECT, p<.004
Lisanby SH et al. Neuropsychopharmacology. 2003.
Faster following MST, p<.01
This information concerns a use that has not been approved by the U.S. Food and Drug Administration
MSTECT
MSTECT
Threshold Suprathreshold Threshold Suprathreshold Threshold Suprathreshold
Syllables Geometric Shapes Nonsense ShapesThreshold Suprathreshold
Vagus Nerve Stimulation Vagus Nerve Stimulation (VNS)(VNS)
FDA approved for epilepsy; FDA FDA approved for epilepsy; FDA approved for TRD July, 2005approved for TRD July, 2005
Implanted in over 30,000 Implanted in over 30,000 patients worldwide patients worldwide
Pulse generator implanted in Pulse generator implanted in left chest wall area, connected left chest wall area, connected to leads attached to left vagus to leads attached to left vagus nervenerve
Mild electrical pulses applied to Mild electrical pulses applied to CN X for transmission to the CN X for transmission to the brainbrain
Vagus Nerve Stimulation Vagus Nerve Stimulation (VNS)(VNS)
Intermittent, cycled Intermittent, cycled stimulationstimulation
30 sec on/5 min off30 sec on/5 min off
24/7 continuous cycles24/7 continuous cycles
In-office programmingIn-office programming (dosing) (dosing) by the treating physicianby the treating physician
Fact that it is an implant helps Fact that it is an implant helps adherence/complianceadherence/compliance
Cervical Vagus Nerve Cervical Vagus Nerve AnatomyAnatomy
~80% afferent fibers, mostly ~80% afferent fibers, mostly unmyelinatedunmyelinated
~20% efferent fibers, mostly ~20% efferent fibers, mostly unmyelinated unmyelinated parasympathetic fibers to parasympathetic fibers to thoraco-abdominal viscerathoraco-abdominal viscera
Some myelinated fibers to Some myelinated fibers to striated muscles of the striated muscles of the pharynx and larynxpharynx and larynx
Henry TR. Neurology. 2002;59(suppl 4):S3-S14.
SolitaryTract
Thalamus
Insula, Anterior Cingulate Gyrus, Orbitofrontal Cortex
Nucleusof the
Solitary Tract
NodoseGanglion
Area PostremaNucleus
CuneatusDMN
Spinal Cord
Medulla
Pons
VagusVagus
Locus Coeruleu
s
VNS: Afferent Pathway to the VNS: Afferent Pathway to the BrainBrain
Parabrachial Nucleus
Hypothalamus
Dorsal Raphe
HippocampusAmygdala
Medial Reticular
Formation
VNS Pivotal Study DesignVNS Pivotal Study Design
Implant
Sham-Control
Treatment Group
Up to 45 days before
implant
2 weeks
2 weeks 8 weeks
Long-Term Phase
Recovery and randomization
Stimulation adjustment Fixed “Dose” VNS Long-Term Phase
Baseline
Rush AJ, et al. Biol Psychiatry. 2005;58:347-354.
Acute outcome at 12-weeksAcute outcome at 12-weeks
10
HAMD24 (Primary Outcome) IDS-SR30 (Secondary Outcome)
% R
esp
on
din
g
1715
7
0
5
10
15
20
VNS Therapy Sham-control
p=0.032p=0.251
Rush AJ, et al. Biol Psychiatry. 2005;58:347-354.
VNS versus Treatment as VNS versus Treatment as UsualUsual
Evaluable observed analysis.
George MS, et al. Biol Psychiatry. 2005;58:364-373.
CGI-I Categorical Outcome at 12 Months
Pivotal study (n=181)Comparative study (n=101)
0
5
10
15
20
25
30
35
40
% o
f P
atie
nts
37
12
pp<0.001<0.001
Much Improved or Very Much
Improved
Safety profile of VNSSafety profile of VNS
3 months (N=232)6 months (N=225)9 months (N=218)12 months (N=209)24 months (N=184)
Most Frequently Reported Stimulation-Related AEs at 3 Months (10%)
Event
1. Rush AJ, et al. Biol Psychiatry. 2005;58:355-363. 2. Cyberonics, Inc. Depression Physician’s Manual. Houston, Tex; 2005.
VNS AdvantagesVNS Advantages Well tolerated with high adherence ratesWell tolerated with high adherence rates
Implant so guaranteed treatment Implant so guaranteed treatment deliverydelivery
No cognitive impairment, or related No cognitive impairment, or related stigmastigma
No weight gain, no known metabolic No weight gain, no known metabolic issues, no sexual dysfunction side effectsissues, no sexual dysfunction side effects
Disadvantages/Disadvantages/ControversiesControversies
Surgery is an obstacle for some patients, Surgery is an obstacle for some patients, and overall costs upfront are high relative and overall costs upfront are high relative to pharmacotherapy and psychotherapyto pharmacotherapy and psychotherapy
Controversy associated with FDA approval, Controversy associated with FDA approval, given failed pivotal trial, has limited access given failed pivotal trial, has limited access in practice for patients – Medicare has in practice for patients – Medicare has decided against covering VNS for TRDdecided against covering VNS for TRD
May be a disincentive for future May be a disincentive for future development of neuromodulation devices development of neuromodulation devices in psychiatryin psychiatry
CMS denial of VNS CMS denial of VNS coveragecoverage
"CMS does not believe there is a treatment "CMS does not believe there is a treatment effect directly attributable to VNS therapy effect directly attributable to VNS therapy based on the current evidence”based on the current evidence”11
““The pivotal randomized, controlled trial of The pivotal randomized, controlled trial of
VNS, subsequent to a pilot study, failed”VNS, subsequent to a pilot study, failed”11
Medicare, however, has covered VNS for Medicare, however, has covered VNS for epilepsy since 1999, where evidence for epilepsy since 1999, where evidence for efficacy is similar to TRDefficacy is similar to TRD
1. www.cms.hhs.gov/MCD/viewdraftdecisionmemo.asp?id=195, accessed 2/13/07
Deep Brain Stimulation Deep Brain Stimulation (DBS)(DBS)
FDA Approved for Parkinson’s FDA Approved for Parkinson’s and Tremorand Tremor
Investigational for OCD, TRDInvestigational for OCD, TRD Stereotactic Target from MRI Stereotactic Target from MRI Two chest-wall Pulse Two chest-wall Pulse
GeneratorsGenerators Burr holes in skull for Burr holes in skull for
electrode placementelectrode placement Stimulation parameters Stimulation parameters
programmed by computer, programmed by computer, through “wand”through “wand”
This information concerns a use that has not been approved by the U.S Food and Drug Administration
DBS Targets - Anterior Limb of the Internal DBS Targets - Anterior Limb of the Internal Capsule/Ventral StriatumCapsule/Ventral Striatum
Approximately where Subcaudate Tractotomy, Gamma Capsulotomy, and DBS Targets Overlap
Motor
Orbital
PremotorDorsolateral
Medial
This information concerns a use that has not been approved by the U.S Food and Drug Administration
Fronto-Basal Projections to Striatum in PrimateHaber SB et al. J of Neuroscience. 1995.
Brown experience with DBS for Brown experience with DBS for
OCD (n=10)OCD (n=10) 35% YBOCS
25% YBOCS
3/10 (6 months)
5/10 (6 months)
YBOCS Severity Improvement During DBS
in Intractable OCD
0
5
15
20
25
30
35
40
Basel
ine
3 M
onths
6 M
onths
YB
OC
S S
core
0
10
20
30
40
50
60
Basel
ine
3 M
onths
6 M
onths
GA
F S
core
FunctionalImprovement During
DBS in Intractable OCD
10
DBS for OCD: Adverse EffectsDBS for OCD: Adverse Effects SurgicalSurgical
Small hemorrhage without symptoms or Small hemorrhage without symptoms or sequelaesequelae
Superficial infectionSuperficial infection Single intraoperative seizureSingle intraoperative seizure
StimulationStimulation Hypomania (4/10)Hypomania (4/10) Sensorimotor effects (facial)Sensorimotor effects (facial) InsomniaInsomnia AutonomicAutonomic Memory flashbacksMemory flashbacks PanicPanic
OFF effectsOFF effects Symptom returnSymptom return
No AEs were persistentNo AEs were persistent
DBS for TRD: piDBS for TRD: pilot Study lot Study n=5n=5
AGEAGE SEXSEX HANDEHANDED-D-
NESSNESS
DIAGNOSISDIAGNOSISDSM-IVDSM-IV
DURATIODURATIONN
OF MDDOF MDD
MEDS/ECT MEDS/ECT RESPONSERESPONSE
000011
5454 MaleMale RightRight Severe/chronic unipolar Severe/chronic unipolar MDD, w/ melancholiaMDD, w/ melancholia
36 years36 years NoneNone
000022
6060 MaleMale RightRight Severe bipolar I Severe bipolar I disorder, MDD w/ disorder, MDD w/
melancholiamelancholia
35 years35 years No sustained No sustained benefitbenefit
000033
5151 FemaleFemale LeftLeft Unipolar MDD w/ Unipolar MDD w/ melancholiamelancholia
19 years19 years NoneNone
000044
5151 FemaleFemale RightRight Unipolar MDD w/ Unipolar MDD w/ melancholiamelancholia
9 years9 years Intermittent Intermittent benefitbenefit
000055
4343 FemaleFemale RightRight Severe unipolar MDD, Severe unipolar MDD, single episode, w/ single episode, w/
melancholic featuresmelancholic features
6 years6 years Minimal, Minimal, short-lived short-lived
improvementimprovement
Greenberg BD et al, Neuropsychopharmacology 29:s32, 2004
Depression Improvement Depression Improvement During DBS in Intractable During DBS in Intractable
DepressionDepression
Greenberg BD et al, Neuropsychopharmacology 29:s32, 2004
Reduced Suicidality During Reduced Suicidality During DBSDBS
Greenberg BD et al, Neuropsychopharmacology 29:s32, 2004
DBS: Subgenual Cingulate (Cg25) DBS: Subgenual Cingulate (Cg25) RegionRegion
Response in 4 of 6 patientsResponse associated with reduction in local and downstream limbic CBF on PET
Mayberg HS et al. Neuron. 2005.
This information concerns a use that has not been approved by the U.S Food and Drug Administration
Deep Brain Stimulation Deep Brain Stimulation (DBS)(DBS)
LimitationsLimitations Limited, short-term, open-Limited, short-term, open-
label data in psychiatry label data in psychiatry
Considerable Surgical RiskConsiderable Surgical Risk
CosmesisCosmesis
Targets and stimulation Targets and stimulation parameters not establishedparameters not established
MRI contraindicationMRI contraindication
Risk of hypomaniaRisk of hypomania
Battery LifeBattery Life
This information concerns a use that has not been approved by the U.S Food and Drug Administration
Neuromodulation Neuromodulation overviewoverview
ECT non-invasive, hospital procedure, requires ECT non-invasive, hospital procedure, requires anesthesia, safe, very efficacious, but anesthesia, safe, very efficacious, but stigmatized, no clear neurology applicationstigmatized, no clear neurology application
TMS is non-invasive, office based, most TMS is non-invasive, office based, most flexible, possible multiple applications, very flexible, possible multiple applications, very acceptable to patients, but is it robust acceptable to patients, but is it robust enough?enough?
VNS bottom-up modulation, limited surgery, VNS bottom-up modulation, limited surgery, but efficacy less than hoped for, & access but efficacy less than hoped for, & access problemsproblems
DBS most invasive, only preliminary data to DBS most invasive, only preliminary data to date (n~50), but looks robustdate (n~50), but looks robust
2121stst century century neuromodulation therapies neuromodulation therapies
in psychiatryin psychiatry Psychiatry treatment may be at similar threshold Psychiatry treatment may be at similar threshold
as cardiology 25 years ago, in terms of potential as cardiology 25 years ago, in terms of potential for devices to improve our therapeutics for devices to improve our therapeutics
Effective medications & psychosocial Effective medications & psychosocial interventions help many but by no means all of interventions help many but by no means all of our patientsour patients
Devices have potential to help our severely ill Devices have potential to help our severely ill patients and clearly warrant intensive research patients and clearly warrant intensive research going forwardsgoing forwards
Post-Lecture ExamPost-Lecture ExamQuestion 1Question 1
Magnetic Seizure Therapy (MST) differs from Magnetic Seizure Therapy (MST) differs from ECT in that:ECT in that:
a.a. the goal is not to induce a therapeutic the goal is not to induce a therapeutic seizureseizure
b.b. the use of focused stimulation to produce a the use of focused stimulation to produce a seizureseizure
c.c. general anesthesia is not requiredgeneral anesthesia is not required
d.d. daily sessions of MST are needed to produce daily sessions of MST are needed to produce a therapeutic effecta therapeutic effect
e.e. it has a more benign profile in terms of it has a more benign profile in terms of cognitive adverse effectscognitive adverse effects
Question 2Question 2The most common side effect reports The most common side effect reports
with VNS is:with VNS is:
a.a. weight gainweight gain
b.b. sexual dysfunctionsexual dysfunction
c.c. cognitive impairmentcognitive impairment
d.d. hoarsenesshoarseness
e.e. chest painchest pain
Question 3Question 3Deep brain stimulation is currently FDA Deep brain stimulation is currently FDA
approved for the treatment of:approved for the treatment of:
a.a. auditory hallucinations in auditory hallucinations in schizophreniaschizophrenia
b.b. chronic neuropathic painchronic neuropathic pain
c.c. obsessive compulsive disorderobsessive compulsive disorder
d.d. parkinson’s Diseaseparkinson’s Disease
e.e. intractable migraineintractable migraine
Question 4Question 4Transcranial Magnetic Stimulation (TMS) Transcranial Magnetic Stimulation (TMS)
differs from Magnetic Resonance differs from Magnetic Resonance Imaging (MRI) technology in that:Imaging (MRI) technology in that:
a.a. the magnetic fields produced are much the magnetic fields produced are much weaker in intensityweaker in intensity
b.b. the rate of change of the magnetic field the rate of change of the magnetic field is higher with an MRI versus TMSis higher with an MRI versus TMS
c.c. MRI technology activates neurons MRI technology activates neurons whereas TMS does notwhereas TMS does not
d.d. scalp discomfort is common with TMS scalp discomfort is common with TMS but not with an MRIbut not with an MRI
Question 5Question 5Which of the following statements about ECT Which of the following statements about ECT
is not true?is not true?a.a. ECT appears to be particularly efficacious ECT appears to be particularly efficacious
in psychotic depressionin psychotic depressionb.b. ECT is not effective in the treatment of ECT is not effective in the treatment of
maniamaniac.c. ECT is effective in the treatment of bipolar ECT is effective in the treatment of bipolar
depressiondepressiond.d. ECT is associate with retrograde memory ECT is associate with retrograde memory
impairmentsimpairmentse.e. ECT is effective in the treatment of ECT is effective in the treatment of
pharmacotherapy-resistant major pharmacotherapy-resistant major depressiondepression