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The (Re)Emerging Role of The (Re)Emerging Role of Therapeutic NeuromodulationTherapeutic Neuromodulation

Philip G. Janicak, M.D.Philip G. Janicak, M.D.Professor of PsychiatryProfessor of Psychiatry

Rush University Medical CenterRush University Medical Center

2012 Current Psychiatry2012 Current PsychiatryAmerican Academy of Clinical Psychiatrists SymposiumAmerican Academy of Clinical Psychiatrists Symposium

March 29, 2012March 29, 2012

Disclosures–Philip G. Janicak, M.D. Grant/Research Support: Cervel Neurotech;

Neuronetics; Otsuka; Sunovion

Consultant/Advisory Board: Bristol-Meyers Squibb; Neuronetics

Speakers’ Bureau: Bristol-Meyers Squibb/Otsuka; Neuronetics

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Major Goals

To review the concept of neuromodulation as an evolving therapeutic strategy

To consider the application of therapeutic neuromodulation for psychiatric disorders with a focus on major depression

To review the definition, indications, administration, efficacy, safety and tolerability for approved therapies

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Major Depression:A Significant Unmet Need

Kessler RC, Berglund P, Demler O, et al. JAMA. 2003;289(23):3095-3105.

• Inadequate response• Intolerant to side effects}3.2 Million

Adequately Treated

4 Million Poorly Served

7.2 Million Treated6.8 Million Untreated

14 Million AdultsU.S.

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Neuromodulation

Induces electrical current in nervous tissue (i.e., neurostimulation)

Based on concept of functional disturbances in distributed neuronal circuits (e.g., corticolimbic mood circuit)

Episodic impact on brain

Usually no sustained systemic effects

© Janicak

Neuromodulation Techniques

•Electroconvulsive Therapy (ECT)•Focal Electrically Administered Seizure Therapy (FEAST)•Magnetic Seizure Therapy (MST)

• Transcranial Magnetic Stimulation (TMS)• Transcranial Direct Current Stimulation (tDCS)

• Deep Brain Stimulation (DBS)• Vagus Nerve Stimulation (VNS)

• Epidural Cortical Stimulation (EpCS)

NON-INVASIVE

INVASIVE

SEIZURESEIZURE NO SEIZURENO SEIZURE

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ECT Disadvantages Access/patient acceptance Optimal administration Adverse effects

• Cognitive

Cost Relapse rates

© Janicak

ECT Adminstration: Maintenance Treatment Strategies

• Medication only• ECT only• ECT plus Medication

CORE Study (n=201)• Li+ plus NT vs ECT• 6-month trial• Relapse rates

• 37% for ECT• 32% for medication

• 50% relapsed or dropped out

8Kellner, Knapp RG, Petrides G, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE).Arch Gen Psychiatry. 2006 Dec;63(12):1337-44.

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Vagus Nerve Stimulation (VNS):Vagus Nerve Stimulation (VNS):DefinitionDefinition

Mild electrical pulses applied to the left vagus nerve in the neck area for transmission to the brain

Left vagus nerve primarily afferent fibers

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VNS Therapy: ComponentsVNS Therapy: Components Dimensions

• Weighs less than 1 ounce and measures 220.27 inches

Location

• Subcutaneously in left chest Function

• Delivers mild pulses at programmed time intervals to left vagus nerve

• Stores selected information Battery life

• Dependent upon dose settings: 3 years at a higher setting, compared to 8 years at a lower setting*

*For the full range of settings in relationship to battery life, see the Physician’s Manual.Cyberonics, Inc. Physician’s Manual for the VNS Therapy™ Pulse Model 102 Generator and VNS Therapy™ Pulse Duo Model 102R Generator. Houston, Tex; 2003. -- Data on file. Cyberonics, Inc.

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Output current Milliamps (mA) 0–3.5 1.0

Signal frequency Hertz (Hz) 1–30 20

Pulse width Microseconds (sec) 130–1000 500

Duty cycle

ON time Seconds 7–60 30

OFF time Minutes 0.2–180 5

VNS Stimulation ParametersVNS Stimulation Parameters

Parameter Units

Range

Median Value at12 Months in Pivotal Study

Stimulation cycle is 24 hours/day.

Cyberonics, Inc. Epilepsy Patient’s Manual for Vagus Nerve Stimulation With the VNS TherapyTM System. Houston, Texas 2002, 2004. -- Cyberonics, Inc. Depression Physician’s Manual. Houston, Tex; 2005.

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VNS: IndicationsVNS: Indications

Treatment-resistant epilepsy*

Treatment-resistant depression*• Adjunctive treatment

• Chronic or recurrent depression

• Failed four or more adequate antidepressant trials

© Janicak*FDA APPROVED

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VNS Acute Study: Response RatesVNS Acute Study: Response Rates

1010

HAMD24 (Primary Outcome) IDS-SR30 (Secondary Outcome)

% R

esp

on

din

g

1717

1515

77

0

5

10

15

20 VNS Therapy

Sham-control

p=0.032p=0.251

Rush AJ, et al. Biol Psychiatry. 2005;58:347-354.

Results: 12-Week Response Rates (LOCF)

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VNS Long-Term Study:VNS Long-Term Study:Response RatesResponse Rates

Rush AJ, et al. Biol Psychiatry. 2005;58:355-363.

0

5

10

15

20

25

30

35

IDS-SR HRSD24

% R

esp

on

se

1414

18181919

22222020

15151717

2323

30302727

1717

2020

2727

32322828

MADRS

Eva

lua

ble

Obs

erve

d an

d LO

CF

Response defined as 50% reduction in IDS-SR30, HRSD24,

MADRS compared with pre-stimulation baseline

3 Months3 Months(n=203-205)(n=203-205)

6 Months6 Months(n=192-197)(n=192-197)

9 Months9 Months(n=184-186)(n=184-186)

12 Months12 Months(n=180-181)(n=180-181)

LOCF Beyond LOCF Beyond 3 Months3 Months

(n=201-202)(n=201-202)

15

0

10

20

30

40

Per

cen

tag

e o

f P

atie

nts

Response Remission

IDS-SR30

Pivotal study (n=180)Pivotal study (n=180)

Comparative study (n=112)Comparative study (n=112)

p=0.029

p=0.006

HAMD24

Response Remission

2222

1515

3030

1717

Pivotal study (n=181)Pivotal study (n=181)

Comparative study (n=104)Comparative study (n=104)

1212

44

1313

77

p=0.003

p=0.031

Evaluable observed analysis. George MS, et al. Biol Psychiatry. 2005;58:364-373.

HAMD24 and IDS-SR30 Categorical Outcomes at 12 Months (Observed Cases)

VNS Comparative Study: Response VNS Comparative Study: Response and Remission Ratesand Remission Rates

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VNS Acute Study: Adverse EventsVNS Acute Study: Adverse Events

43% 45%

11%

Cyberonics, Inc. Depression Physician’s Manual. Houston, Tex; 2005.

AEs were analyzed according to severity rating

• Mild AE: transient and easily tolerated

• Moderate AE: discomfort and interrupted usual activities

• Severe AE: considerable interference with usual activities

47%45%

8%

Pivotal StudySham-Control Group (3 Months)

Pivotal StudyVNS Group (3 Months)

Mild

Moderate

Severe

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VNS Long-Term Study:VNS Long-Term Study:Adverse EventsAdverse Events

3 months (N=232)6 months (N=225)9 months (N=218)12 months (N=209)24 months (N=184)

Rush AJ, et al. Biol Psychiatry. 2005;58:355-363.Cyberonics, Inc. Depression Physician’s Manual. Houston, Tex; 2005.

AEs 10%

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Transcranial Magnetic Stimulation Transcranial Magnetic Stimulation (TMS): Definition(TMS): Definition

Pulsed magnetic fields of ~1.5 Tesla in strength

Magnetic fields pass unimpeded approximately 2–3 cm into cortex

Induces a focal electrical current in cortical tissue

Produces local and distal functional changes in targeted neural circuitry

TMS: Components

Electrical source Large capacitors Magnetic stimulator Cable with minimal resistance Stimulating coil

Computer program produces a pattern of magnetic

pulses over a brief timeframe

19© Janicak

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TMS: Stimulation ParametersTMS: Stimulation Parameters Motor threshold (80–120%) Frequency (<1 Hertz; 1–20 Hertz)

• Single versus repetitive (rTMS)

• Slow versus rapid rTMS

Stimulation train Intertrain intervals

© Janicak

TMS: Indications Unipolar major depression*

Bipolar disorder Anxiety-related disorders

• Generalized anxiety

• Obsessive-compulsive disorder

• Posttraumatic stress disorder

• Panic disorder

Schizophrenia and schizoaffective disorder Substance dependence Other disorders (e.g., migraine headaches)

21© Janicak

*FDA APPROVED

TMS: Study Design

O’Reardon JP, Solvason B, Janicak PG, et al. Biol Psychiatry. 2007;62:1208–1216.; Janicak PG, O’Reardon J, Sampson SM, et al. J Clin Psychiatry. 2008;69(2):222–232.; Avery DH, Isenberg KE, Sampson SM, et al. J Clin Psychiatry. 2008;69(3):441-451; Lisanby SH, Husain MM, Rosenquist PB, et al. Neuropsychopharmacology. 2009,34:522–534.; Janicak PG, Nahas Z, Lisanby SH, et al. Brain Stimul. 2010;3(4):187-199.

Maintenance ofMaintenance ofEffect StudyEffect Study2,4,52,4,5

‘103’‘103’

Open-LabelOpen-LabelCrossover StudyCrossover Study 2,3,42,3,4

‘102’‘102’

Randomized, Randomized, Controlled StudyControlled Study1,2,41,2,4

‘101’‘101’

Not Improved

Improved

Improved

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-8

-6

-4

-2

0Baseline Week 2 Week 4 Week 6

Ch

ang

e F

rom

Bas

elin

e

P=.191P=.057 P=.058

-8

-6

-4

-2

0Baseline Week 2 Week 4 Week 6

Ch

ang

e F

rom

Bas

elin

eP=.051

P=.012 P=.015

TMS:Efficacy in Overall Population

MADRS Total Score(Baseline to Endpoint Change)

HAMD-24 Total Score(Baseline to Endpoint Change)

Active TMS (n=155)

Sham TMS(n=146)

* P<.05. LOCF, LS mean.O’Reardon JP, Solvason B, Janicak PG, et al. O’Reardon JP, Solvason B, Janicak PG, et al. Biol PsychiatryBiol Psychiatry. 2007;62:1208–1216.. 2007;62:1208–1216.

* *

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TMS: Response and Remission Rates

O’Reardon JP, Solvason B, Janicak PG, et al. O’Reardon JP, Solvason B, Janicak PG, et al. Biol PsychiatryBiol Psychiatry. 2007;62:1208–1216.. 2007;62:1208–1216.

Active TMS Sham TMS

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P=.007P=.0006 P=.0041

TMS:Efficacy in Indicated Population

MADRS Total Score(Baseline to Endpoint Change)1

HAMD-24 Total Score(Baseline to Endpoint Change)2

** P<.01.LOCF analysis of evaluable study population.1. Lisanby SH et al. Neuropsychopharmacology. 2009;34(2):522-534; 2. Data on file. Neuronetics, Inc: Malvern, PA; 2008.

Active TMS(n=88)

Sham TMS(n=76)

**** **

Baseline Week 2 Week 4 Week 6

0

-2

-4

-6

-8C

han

ge

Fro

m B

asel

ine

**** **P=.0018

P=.0006 P=.0063

Baseline Week 2 Week 4 Week 6

0

-2

-4

-6

-8

Ch

ang

e F

rom

Bas

elin

e

TMS: Maintenance of Effect Study 99 patients entered 24-week durability phase

on antidepressant maintenance monotherapy 10 (12.9%) patients relapsed 38 (38.4%) met criteria for symptom

worsening• 32/38 (84%) reachieved symptomatic benefit with TMS

reintroduction

Safety and tolerability were similar to TMS monotherapy

Janicak PG, Nahas Z, Lisanby SH, et al. Brain Stimulation 2010. (in press). 26

NIMH OPT-TMS: Study Design Medication-free, TRD subjects (n=190) Active versus sham TMS, same stimulation

parameters to left DLPFC as industry trial; improved sham control; MRI-guided targeting

Flexible duration, an initial 3-weeks (15 sessions) with the option for additional 3-weeks if improving

Primary outcome was remission at exit

George MS, Lisanby SH, Avery D, et al. Arch Gen Psychiatry 2010;67(5):507-516. 27

NIMH OPT-TMS: Study Results

TMSSham

P<0.015

Odds ratio = 4.2;Odds ratio = 4.2;P<0.02P<0.02

NNT=12NNT=12 TMS Sham

Remission

0%

5%

10%

15%

28George MS, Lisanby SH, Avery D, et al. Arch Gen Psychiatry 2010;67(5):507-516.

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TMS vs ECTTMS vs ECT

No seizure necessary

No anesthesia

No cognitive disruption

No drug interaction issues

Subjects remain independent

© Janicak

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TMS vs ECT Literature Summary 5 of 9 trials reported antidepressant

equivalence

• 1 trial reported UND/BL ECT to be superior to TMS

• 1 trial reported BL ECT to be superior to TMS

• 1 trial found UND/BL ECT plus medication superior to TMS monotherapy in MDD with psychosis but comparable in efficacy to TMS for MDD without psychosis

• 1 trial found improvement with both but ECT>TMS for mood and suicidality

Janicak PG, Dowd SM, Rosa M, et al. Transcranial magnetic stimulation versus electroconvulsive therapy for the treatment of more severe major depression. In: Marcolin MA, Padberg F, eds. Transcranial brain stimulation for treatment of psychiatric disorders (Advances in Biological Psychiatry). Basel, Switzerland: Karger. 2007;23:97–109.

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TMS: Common Adverse Events

Janicak PG, O’Reardon J, Sampson SM, et al. Janicak PG, O’Reardon J, Sampson SM, et al. J Clin PsychiatryJ Clin Psychiatry. 2008;69(2):222–232.. 2008;69(2):222–232.

Prestudy 1 2 3 4 5 6 7 8 9

Week

50

45

40

35

30

25

20

15

10

5

0

No

. of

Eve

nts

70

60

50

40

30

20

10

0

Prestudy 1 2 3 4 5 6 7 8 9

Week

No

. of

Eve

nts

Time Course of Incidence of Headache in RCT

Time Course of Incidence of Application-Site Pain in RCT

Active TMS (n=155)

Sham TMS(n=146)

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TMS: Serious Adverse EventsTMS: Serious Adverse Events

Active TMS(N=165)N (%)

Sham (N=158)

N (%)Serious Adverse Events

Janicak PG, O’Reardon J, Sampson SM, et al. J Clin Psychiatry 2008;69(2):222-232.

TMS: Safety I

No seizures; deaths or suicides

Minimal systemic effects No adverse effect on cognition Most common adverse events

were headache and scalp discomfort during treatment

<5% of patients discontinued due to adverse events

No seizures; deaths or suicides

Minimal systemic effects No adverse effect on cognition Most common adverse events

reported were headache and scalp discomfort

5.5% (n=5) of patients on active TMS discontinued due to adverse effects

TMS Study NIMH Study

Janicak PG, O’Reardon J, Sampson SM, et al. J Clin Psychiatry 2008;69(2):222-232.;George MS, Lisanby SH, Avery D, et al. Arch Gen Psychiatry 2010;67(5):507-516. 33

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TMS: Safety II Precautions

• Pregnancy• Children and adolescents• Heart disease• Medication pumps• Medication that may lower the seizure threshold

Warnings• Implanted device activated or controlled by physiologic signals, even

if the device is located outside the 30 cm distance.• Wearable or implantable cardioverter defibrillators

Contraindications

• Conductive, ferromagnetic, or other magnetic sensitive metals that are implanted or are non-removable within 30 cm of the treatment coil (excludes dental hardware)

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Deep Brain Stimulation (DBS): Definition

Delivery of electrical stimulation

Produced by an internal pulse generator

Administered to specific CNS locations

Chronically implanted electrodes

Minimal tissue injury

© Janicak

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DBS: Components/ParametersDBS: Components/Parameters A brain lead (1.27 mm in diameter) is stereotactically

implanted onto specific brain targets The stimulator leads are connected by a wire to

pulse generators, usually placed in the chest Parameters such as frequency (2 to 185 Hz),

intensity (0 to 10.5 volts), and pulse width (60 to 450 μs) are programmable

Stimulators can also be programmed to vary in several respects (e.g., continuous versus intermittent stimulation)

© Janicak

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Parkinson’s disease

Tremors

Dystonia

Refractory obsessive-compulsive disorder (OCD)

Treatment-resistant depression (TRD)*

DBS: Indications

© Janicak*NOT FDA APPROVED

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DBS: Efficacy in TRD

Chronic stimulation to modulate overactivity of the Chronic stimulation to modulate overactivity of the subgenual cingulate gyrussubgenual cingulate gyrus and impact and impact downstream targetsdownstream targets

Maximum benefit delayedMaximum benefit delayed and progressiveand progressive, , plateaued at 6 months and was sustained for up plateaued at 6 months and was sustained for up to 12 monthsto 12 months

PET demonstrated PET demonstrated alterations inalterations in blood flowblood flow No adverse No adverse cognitive effectscognitive effects

Mayberg, et al, Neuron. 2005.; Lozano, et al. Biological Psychiatry. 2008.

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Percent of Subjects Meeting Criteria for Percent of Subjects Meeting Criteria for Response or Remission by TimeResponse or Remission by Time

Patients meeting response or remission criteria after DBS. The proportion of patients responding or reaching remission increased over time to plateau from 6 to 12 months.

Mayberg, et al, Neuron. 2005.; Lozano, et al. Biological Psychiatry. 2008.

0

10

20

30

40

50

60

70

Months Post-DBS

Pe

rce

nt

of

Su

bje

cts

Percentage ofResponders

Percentage ofRemitters

Percentages of Patients With Treatment-Resistant Depression (N=20) Who Responded or Remitted

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Response was defined as a reduction of ≥50% from baseline in Hamilton Depression Rating Scale (HAM-D) score; remission was defined as a HAM-D score ≥7.

Kennedy, Giacobbe, Rizvi, et al. Am J Psychiatry 2011;168:502-510.

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Surgical procedure (e.g., seizure, bleeding, infection)

Device (e.g., lead breakage, malfunctioning)

Stimulation(e.g., paresthesias, muscle contractions, mood changes)

DBS: Adverse Effects

© Janicak

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Potential RolePotential Roleof Therapeutic Neuromodulationof Therapeutic Neuromodulationfor Psychiatric Disorders Ifor Psychiatric Disorders I

• Organic psychosis (e.g., refractory Parkinson’s syndrome)

• Catatonia unresponsive to medication

• NMS unresponsive to medication

Bright light therapy Switch/Augmentation Strategies

(seasonal pattern)

(insufficient response)• Prior response to ECT only• High risk• Patient preference• Psychotic depression• Manic delirium

TMS/w/ and w/o medication

ECT

(insufficient response)

(insufficient response)(insufficient response) (insufficient response)

ANTIDEPRESSANT(if psychotic, consider AP as well) LITHIUM/VPA/SGA

SCHIZOPHRENIC EPISODESCHIZOPHRENIC EPISODE

ANTIPSYCHOTIC

MANIC EPISODEMANIC EPISODEMAJOR DEPRESSIVE EPISODEMAJOR DEPRESSIVE EPISODE

© Janicak04/21/23

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• Nonemergent • Prior good response to unilateral, nondominant ECT

• High risk (e.g., acutely suicidal) • Prior poor response to unilateral,

nondominant ECT

Unilateral, nondominant ECT (2.5-6.0 x seizure threshold)

(insufficient response)Bilateral ECT (excessive cognitive

adverse effects)

(chronic, relapsing)

• Maintenance medication (e.g., lithium plus NT)• Maintenance ECT (± medication)• Maintenance TMS/VNS (± medication)• Possibly DBS

Adapted from: Janicak PG, 2006

ECT

Potential Role of Therapeutic Potential Role of Therapeutic Neuromodulation for Psychiatric Neuromodulation for Psychiatric Disorders IIDisorders II

© Janicak04/21/23 43

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Major Goals

To review the concept of neuromodulation as an evolving therapeutic strategy

To consider the application of therapeutic neuromodulation for psychiatric disorders with a focus on major depression

To review the definition, indications, administration, efficacy, safety and tolerability for approved therapies

Janicak PG, Dowd SM, Rado JT, Welch MJ. The (re)emerging role of Janicak PG, Dowd SM, Rado JT, Welch MJ. The (re)emerging role of therapeutic neuromodulation. therapeutic neuromodulation. Curr PsychiatryCurr Psychiatry 2010;9(11)66-74. 2010;9(11)66-74.

Janicak PG, Nahas Z, Solvason SH, et al. Durability of clinical benefit with Janicak PG, Nahas Z, Solvason SH, et al. Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study. month, multisite, open-label study. Brain Stimul Brain Stimul 2010;3(4):187-199.2010;3(4):187-199.

Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial magnetic Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depressive: stimulation versus electroconvulsive therapy for major depressive: preliminary results of a randomized trial. preliminary results of a randomized trial. Biol PsychiatryBiol Psychiatry. 2002;51:659–667.. 2002;51:659–667.

Janicak PG, Dowd SM, Rosa M, et al. Janicak PG, Dowd SM, Rosa M, et al. Transcranial magnetic stimulation Transcranial magnetic stimulation versus electroconvulsive therapy for the treatment of more severe major versus electroconvulsive therapy for the treatment of more severe major depression. In: Marcolin MA, Padberg F, eds. Transcranial brain stimulation depression. In: Marcolin MA, Padberg F, eds. Transcranial brain stimulation for treatment of psychiatric disorders (Advances in Biological Psychiatry). for treatment of psychiatric disorders (Advances in Biological Psychiatry). Basel, Switzerland: Karger. 2007;23:97–109.Basel, Switzerland: Karger. 2007;23:97–109.

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References IReferences I

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References IIReferences II Janicak PG, O’Reardon J, Sampson SM, et al. Transcranial magnetic stimulation in Janicak PG, O’Reardon J, Sampson SM, et al. Transcranial magnetic stimulation in

the treatment of major depressive disorder: a comprehensive summary of safety the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction experience from acute exposure, extended exposure, and during reintroduction treatment. treatment. J Clin PsychiatryJ Clin Psychiatry. 2008;69(2):222. 2008;69(2):222––232.232.

Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: transcranial magnetic stimulation in the acute treatment of major depression: Clinical predictors of outcome in a multisite, randomized controlled clinical trial. Clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology.Neuropsychopharmacology. 2009;34(2):522 2009;34(2):522–534–534..

Lozano AM, Mayberg HS, Giacobbe P, et al. Subcallosal cingulate gyrus deep Lozano AM, Mayberg HS, Giacobbe P, et al. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. brain stimulation for treatment-resistant depression. Biol Psychiatry.Biol Psychiatry. 2008;64:461 2008;64:461––467.467.

O’Reardon JP, Solvason B, Janicak PG, et al. Efficacy and safety of transcranial O’Reardon JP, Solvason B, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. randomized controlled trial. Biol PsychiatryBiol Psychiatry. 2007;62:1208. 2007;62:1208––1216.1216.

Pilitsis JG, Bakay AE. Deep brain stimulation for psychiatric disorders. Pilitsis JG, Bakay AE. Deep brain stimulation for psychiatric disorders. Psychopharm ReviewPsychopharm Review. 2007;42(9):67. 2007;42(9):67––74.74.