Brain Stimulation Brain Stimulation Therapies for Therapies for Treatment Resistant Treatment Resistant Depression Depression John P. O’Reardon, MD John P. O’Reardon, MD Associate Professor, Associate Professor, Department of Psychiatry Department of Psychiatry Director, TMS Laboratory and Director, TMS Laboratory and Treatment Resistant Treatment Resistant Depression Clinic Depression Clinic University of Pennsylvania University of Pennsylvania
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Brain Stimulation Therapies for Treatment Resistant Depression John P. O’Reardon, MD Associate Professor, Department of Psychiatry Director, TMS Laboratory.
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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
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
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
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
Fast (20 Hz) TMS - Fast (20 Hz) TMS - excitatoryexcitatory
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
* 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
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)
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
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
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
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
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
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
Answers to Pre and Post-Answers to Pre and Post-Lecture ExamsLecture Exams