Hilik Levkovitz MD,MHA

Director Day Hospital & Cognitive and Emotional Lab.

School of Medicine, Tel Aviv University

Israel.

Deep Transcranial Magnetic Stimulation (deep TMS) for Major

Depression:A Large Multicenter Study

Transcranial Magnetic Stimulation (TMS) Principe of Action

TMS is a noninvasive technique used to apply magnetic pulses to the brain. The pulses are administered by passing high currents through an electromagnetic coil that induce electrical currents in the underlying cortical tissue, thereby producing a localized axonal depolarization .

Head

Suppor

t

First Generation Second Generation

Multicenter studies, O’Reardon 2007, George 2010

• Improve antidepressant effect of rTMS

• Establish long-term efficacy of rTMS

• Develop protocols for therapy-resistant

MDD

The Challenges in the Field of rTMS:

Introduce a New Design TMS Coils the H-Coils

• The H-coils stimulate deep brain areas• Different coils target to different brain areas

Roth et al. J. Clin. Neurophysiology 2007

H1L Coil (120% MT)H1 Coil (120% MT)

E [V/m]

H2 Coil (120% MT)

RED AND RED AND ORANGE ORANGE COLORS COLORS

REPRESENT REPRESENT BRAIN BRAIN

ACTIVATIONACTIVATION

Phantom Brain MeasurementsElectric field distribution

of the H coils and superficial coil at 120% MT

Figure of 8 Coil (120% MT)

While superficial coil stimulate 1-1.5 cm the H coils reach to 5-6 cm

beneath the cortex

Roth et al. J. Clin. Neurophysiology 2007

Acute feasibility and safety study in Depression

LR LR LR LR

Left BilateralPartial Left Superficial coil

H1 deep TMS (1Hz) disrupts mPFC functional connectivity during rest

b

P<0.001Sham TMS subjects

Figure-8 subjectsDeep TMS subjects X=-5

PF

aDeep TMS subjects

Figure-8 subjectsSham TMS subjects

X=-9

Front Hum Neuroscience. 2011

Overview of Clinical Trials in Depression

Safety in normal volunteers (n=35 )

Clin Neurophysiol. 2007

Acute feasibility and safety study in MDD (n=63) Brain Stimul. 2009

Long-term feasibility and safety study

in MDD (n=30) World J Biol Psychiatry 2012

Randomized, controlled, multi-centre study

(efficacy) (n=212)

Objective

To explore the efficacy and safety of H-coil deep brain rTMS in subjects with MDD.

Design

A randomized, 16 week, double blind, sham control, multi-center trial.

Study Objective & Design

21 sites (15 from North America , 2 from Europe and 4 from Israel) participate in the study and this was one of

the biggest studies in the field of TMS.

International sites include:

Criterion for Randomization:HDRS-21 within

±30%

Screening and Washout Period

Treatment Trial Period

2 wks 16 wks4 weeks of 5 daily

active/sham treatments

(20 treatments)

12 weeks of biweeklyactive/sham treatments

(24 treatments )

Ran

dom

izati

on

ACTIVE TMS

SHAM TMS

Scre

en

in

g

Baselin

e

Prefrontal rTMS (18 Hz, 2s on 20s off) over a 20‑min period each morning for 4 consecutive weeks (5 days a week), to a total of 1980 stimuli per

day.

Study Flowchart

* Throughout the study,

the drop-out rate was

higher in the control

group compared to

the treatment group.

Recruitment Details

420 patients signed an informed

consent form

212 patients (55%) were randomized to one of the

study groups

Prospective, Multicenter, Double-Blind, Randomized, Sham Controlled Trial

•212 MDD patients•HDRS > 20 at screening.• Did not response or tolerate at least one

antidepressant medications in the current episode

•Trial duration 18 weeks•2 week of wash-out medication•4 weeks of 5 daily treatments •12 weeks of biweekly maintenance treatments

•Change from baseline in HDRS-21 scores at week 5 post-randomization

•Response rate (at 5 and 12 week post-randomization)

•Remission rates•Quality of Life

PatientsPatients

TreatmenTreatmentt

Primary Endpoint

SecondarSecondary y

EndpointEndpointss

Prospective, Multicenter, Double-Blind, Randomized, Sham Controlled

Trial

No response

Intolerance

Number of previous antidepressants for

current episode

1 2 3 4 5 6

Inclusion Criteria number of medication in current episode

Demographics - DataTreatment GroupSham Group

Age (Years)44.9 ± 11.6048.5 ± 11.71

Gender (% Men)54%52%

Age of first episode25.8 ± 12.1427.8 ± 13.09

Current episode duration (months)

21.9 ± 16.3720.2 ± 15.13

Suicidal history (% no attempt)90%93%

HDRS score at study beginning 23.7 ± 4.4023.2 ± 3.87

Sham Device Causes Sensations of:

Tingling.

Pain.

Twitching of facial muscles.

70% of subjects thought they were receiving real

treatment: 80% from the active group and 60% from the

sham group

Primary end point: Change in depression

*

Slope of change dTMS = -6.39 points, Sham=-3.28 points* P-value of difference= 0.008 in per protocol sample P-value = 0.05 in intent to treat analysis

Remission and Response at Week 5

38.4%

21.3%

32.6%

14.6%

P=0.021*

P=0.014*

Response- Improvement of at least 50% from baseline

Remission and Response End of Study

46.8%

25.3%

32.9%

21.7%

P=0.004*

P=0.10*

Change in depression & history of failed on antidepressant

medications

Subjects who failed >2 medications in the current episode, showed a significant improve on deep TMS treatment relative to sham.

Response and remission & history of failed on antidepressant

medications

Subjects who failed >2 medications in the current episode, showed a significant response to the deep TMS treatment relative to sham.

Safety outcomes

The vast majority of patients experienced the

treatment well and with no side effects.

The most common adverse events were:

Mild headaches.

One subject (female, 26 years old) experienced a

seizure during the active treatment following excessive

consumption of alcohol on the night before treatment.

Summery

The efficacy of the treatment was evidenced according to the study

objectives, defined in coordination with the FDA.

The side effects observed during the study are typical and expected

in TMS treatments and they comply with the safety demands that

were approved in the study protocol by the FDA.

Thanks

USA- John Hopkins University- Medical University of South Carolina - Harvard Medical School- UC Davis Center for Mind and Brain – Sacramento- University of California- NewYork State Psychiatric Institute - Gateway Hospital & Mental Health Center - California

CANADA- Center for Addiction and Mental Health - Toronto

GERMANY- University of Bonn - Ludwig-Maximilians-University - Munich

ISRAEL- Shalvata Mental Health Center - Be'er Ya'acov Mental Health Center- Kfar Shaul Mental Health Center- Hadassah Medical Center

A. Zangen and Y. RothShalvata & Brainsway Team

USA - Duke Institute for brain sciences-Southwestern Medical Center at Dallas