The Antidepressant Efficacy of Repetitive Transcranial Magnetic Stimulation ( rTMS) as add-on to Electroconvulsive Therapy (ECT). A Double Blind Randomized Controlled Trial.
Phase: NA
Conditions: Depression
Sponsor: University of Aarhus

 
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The antidepressive effect of low frequency rTMS as 
addon to ECT. A pilot study   
  
The original  dated 13.04.2015 written in Danish  
Translated to English  11.12.20 (the submitted form)  
   
  
NCT02123485    
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Introduction   
rTMS (repetitive transcranial magnetic stimulation) is a potential new  

 
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noninvasive antidepressant method, which implies non-convulsive focal 
stimulation of the brain through a time varying magnetic field. rTMS is based on 
the principle of electromagnetism. An electromagnetic coil placed on the scalp 
produces an oscillating magnetic field that penetrates the scalp and skull 
unattenuated and gives rise to a current in the adjacent parts of the cerebral 
cortex as well as functionally connected centers of the brain. Previous research 
indicates that the antidepressant effect of rTMS is associated with specific 
stimulation of the dorsolateral prefrontal cortex. The stimulus frequency has 
been shown to play a key role in the mechanisms of action of rTMS. Preclinical 
studies  have revealed that low frequency rTMS is associated with long-term 
inhibition of neuronal activity (long-term depression), while high frequency 
stimulation is followed by prolonged activation (long-term potentiation). To 
some extent, this differential effect of the two types of frequencies are reflected 
in human studies.    
The majority of clinically controlled studies on the antidepressant efficacy of 
rTMS have used high frequency stimulation of left prefrontal cortex supporting 
the evidence of the antidepressant efficacy of this treatment model, which has 
been approved by the FDA in USA and later in the EU for the treatment of 
depression . Fewer studies have used right prefrontal low frequency rTMS, 
though this model of stimulation obviously has fewer side effects, such as local 
discomfort and a lower risk of releasing epileptic seizures, than high frequency 
stimulation . Both stimulus models have been shown to have a statistically and 
clinically significant antidepressant effect of equal magnitude as add-on to other 
antidepressant treatments including ECT.    
ECT is used in approximately 5% of all psychiatric patients in Denmark with 
slightly increasing frequency of 11% since 1999.  ECT acts through epileptic 
seizures and have a documented anti-kindling effect involving limbic and 
paralimbic structures. This kindling repressing effect is probably of significance 
for the mechanism of ECT. rTMS does not work by inducing seizures, but like 
ECT low frequency rTMS has been shown to inhibit amygdala-kindled seizures in 
animal studies. Therefore, theoretically it is possible that low frequency rTMS 
can amplify the antidepressant effect of ECT.   
The present study will be carried out to investigate in which degree right 
prefrontal low frequency rTMS administered as add-on may accelerate the 

 
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antidepressant effect of ECT and thus minimize the side-effects of this 
treatment.    
   
 
  
Material and methods   
Design   
The present study will be carried out as a randomized, clinically controlled, 
double blind investigation comparing conventional ECT + sham-stimulation with 
ECT + right prefrontal low frequency rTMS. Previous research concerning the 
antidepressant effect of ECT versus rTMS has found remission rates on ECT 
between 50 and 60%. On the basis of these figures and the outcome of 
previous RCT studies on the antidepressant effect of low frequency rTMS 
compared to placebo the difference in the incidence of remission was expected 
to be 20-30%. A rate difference of 20% would require 81 patients, while a rate 
difference of 30% would require 31 patients in each group to have 80% power 
in a 2-sided test at a 5% significance level.                                                             
   
   
Randomization   
The patients are randomly allocated to ECT + rTMS or ECT + sham   
According to the principle of block randomization. Six blocks are created with 10 
sealed opaque envelopes in each, half of them containing a treatment code for 
rTMS and the other half for ECT. The envelopes in each block are shuffled 
thoroughly and numbered from one to 10. To ensure allocation concealment, 
the patients were randomly allocated to treatment by an independent third 
part.   
   
   
Ethics   
The study meet the criteria of the Helsinki Declaration II. The patients’ consent 
is  based on written and oral information, and the regional ethics committee 
approved the project protocol.   
   
Study Population   
The study population covers inpatients with depression from the County of   

 
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Aarhus. The patients are admitted to the department for Depression and 
Anxiety, Aarhus University Hospital, Risskov, Denmark, and recruited primarily 
from the city of Aarhus with associated rural districts, a catchment area of 
approximately 300,000 inhabitants.   
Inclusion criteria:   
Age between 18 and 80 years and a total score on 17-item HAM-D (24) of 20 or 
higher and/or 9 or higher on the subscale.    
All patients fulfill the ICD-10 criteria for moderate to severe depression and the 
Diagnostic and Statistical Manual of Mental Disorders-IV criteria for major 
depressive disorder. Unipolar as well as bipolar patients are included.    
Exclusion criteria:   
Patients with organic brain damage, personal or family history of epileptic 
seizures, metallic objects in the chest or brain, cardiac pacemakers, and 
somatic diseases associated with brain dysfunction were excluded from the 
study. Pregnancy, use of coercive measures, severe suicidal risk, severe 
agitation or delirium, and alcohol or drug dependence (ICD-10) constituted 
additional exclusion criteria.   
General physical and neurological examination will be supplied by routine blod 
tests and an electrocardiogram.    
Outcome measures   
Primary effect measures: percentage of response and remission.    
Secondary outcome measures: change in cognitive function.    
Depression severity is evaluated using the Hamilton 17-item, the 6-item scale 
for depression (HAM-D6) and the Major Depression Inventory scale (MDI) 
Response defined as a 50 % reduction in total HAM-D score and remission as a 
total HAM-D (17-item) score of 8 or lower.    
Adverse effect is further assessed by a scale based on the Udvalg for Kliniske 
Undersoegelser (UKU: Committee for Clinical Investigations) side effect rating 
scale    
Changes in the degree of depression and adverse effects will be assessed at 
baseline (before treatment) at weekly intervals within 24 hours after 3. 6. and 
9. ECT. Additional HAM-D, MDI´s and UKU ratings are carried out 4 weeks after 
termination of the treatment period. Trained clinicians carry out quantitative and 
diagnostic  ratings.    

 
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The cognitive function. Patients will be assessed before each treatment 
course, within 48 hours and 4 weeks after last ECT. Global cognitive functioning 
is assessed with a short test battery comprising measures of attention and 
speed (Trail-Making Tests A and B, visual and verbal memory and learning (Rey  
Complex Figure Test, Logical Memory/ Wechsler Memory Scale Revised, and 
Executive Function as in Verbal Fluency semantically and phonologically.   
   
Pharmacological Treatment   
Concomitant antidepressant treatment  is monitored continuously during the 
investigation. During the treatment period (from baseline until the end of week   
3), psychopharmacological treatment is held constant. If possible, 
benzodiazepines will be  tapered off 2 to 3 days before the first ECT. In case of 
severe anxiety, oxazepam will be used before 5 PM the day before treatment. If 
sleeping medication was needed, zolpidem or quetiapine will be  preferred. 
Antiepileptic's prescribed as mood stabilizers are discontinued (lamotrigine dose 
was halved) before the first treatment. After termination of the treatment 
period, the patients continue any psychopharmacological medication with no 
restrictions.   
   
rTMS treatment  was carried out by a MagPro type R30 (MagVenture A/S, 
Lucernemarken 15, 3520 Farum, DK) stimulator, which is certified by the EU 
for treatment of depression, using a water-cooled double blind, figure eight 
placebo spool (type Cool-B65 A/P Butterfly Coil.   
The motor threshold will be determined by placing the center of the coil on a 
line connecting the vertex with the auditory meatus, stimulating the cortex to 
find the lowest intensity that produced a visual motor response in the tenar of 
the left hand. The treatment site over the right dorsolateral prefrontal cortex is 
then found by moving the coil 5 cm anterior to this point at a right angle to the 
line connecting the auditory meatus and the vertex.    
The patients receive either placebo stimulation or two 180-second 1-Hz trains 
delivered at an intensity of 110% of motor threshold with a 180 seconds 
intertrain interval. This procedure is followed two times a week on ECT-free 

 
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days ie. on Tuesdays and Thursdays as ECT is delivered on Mondays, 
Wednesdays, and Fridays.    
   
Blinding   
The result of the randomization (active or sham rTMS) will be downloaded by an 
independent third part to a patient Key (USB memory stick) that will be sent to 
the treatment center and inserted in the MagPro stimulator.    
The coil, which is identical on both sides, had a built-in position sensor used to 
ensure that the correct (active or sham) side of the coil faced towards the 
patient's head. If the coil position is wrong, the operator receive the display 
message a "Flip Coil" prompt on the MagPro screen. To ensure blinding of 
patients, electrodes from the MagPro will be used to stimulate the patient's skin 
in the coil area to mimic real rTMS.    
   
Electroconvulsive Therapy   
Thymatron (Fred Berninger Import OHG, Taufkirchen, Germany) (maximum 
dose of stimulation, 1008 milli coulombs) is used for ECT. Patients elected for 
this type of treatment received 9 ECTs on the average during the project 
period. The treatment is administered 3 times weekly with handheld electrodes 
according to the guidelines of the Danish Psychiatric Society .   
   
   
Statistics   
Treatment and placebo groups will be compared based on a t-test or chi-square 
test dependent on which was most suitable. The effect of treatment on 
HAMD6,HAM-D17 and  MDI over time will be evaluated based on a last 
observation carried forward as well as quadratic linear mixed model. The effect 
of treatment on cognitive function over time will be  evaluated based on a linear 
mixed model.