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TRANSCRIPT
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