Treatment of Depression in the Elderly With Repetitive Transcranial Magnetic Stimulation (rTMS) Using Theta-burst Stimulation (TBS): Randomized, Double-blind, Sham-controlled, Clinical Trial
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: University of Sao Paulo

 
RESEARCH PROJECT 
 
 
 
 
 
 
TREATMENT OF DEPRESSION IN THE ELDERLY WITH REPETITIVE 
TRANSCRANIAL MAGNETIC STIMULATION (RTMS) USING THETA- 
BURST STIMULATION (TBS): RANDOMIZED, DOUBLE-BLIND, 
SHAM- CONTROLLED, CLINICAL TRIAL 
 
 
 
 
 
 
 
 
 
 
ClinicalsTrials.gov.br identifier: NCT04842929 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
October 2021 
 

Treatment of Depression in the Elderly with repetitive transcranial magnetic stimulation 
(rTMS) using theta-burst stimulation (TBS): study protocol for a randomized, double-blinded, 
controlled trial 
 
 
 
Leandro Valiengo1, 2, 3; Bianca S. Pinto1; Kalian A. P. Marinho1; Leonardo A. Santos1; Luara C. Tort1; 
Rafael G. Benatti1; Bruna B. Teixeira1; Cristiane S. Miranda1; Henriette B. Cardeal1; Paulo J. C. Suen1; 
Julia C. Loureiro1; Renata A. R.Vaughan1; Roberta A. M. P. F. Dini Mattar1; Maíra Lessa; Pedro S. 
Oliveira1; Valquíria A. Silva1; Wagner Farid Gattaz 2; André R Brunoni,1, 2*; Orestes Vicente Forlenza2* 
 
 
 
 
 
1. 
Serviço Interdisciplinar de Neuromodulação (SIN), Departamento e Instituto de Psiquiatria, 
Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, SP, Brasil. 
2. 
Laboratório de Neurociências (LIM-27), Departamento e Instituto de Psiquiatria, Hospital das 
Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, SP, Brasil. 
3. Programa de fisiopatologia experimental, Faculdade de Medicina, Universidade de São Paulo, SP, 
Brasil. 
 
* these authors contributed equally to this work 
 
 
 
 
 
 
Running title: Magnetic Randomized Trial in Elderly Depressed (Mr. TED) 
ClinicalsTrials.gov.br identifier: NCT04842929 
Site: https://clinicaltrials.gov/ct2/show/NCT04842929 
 
 
 
Corresponding author: 
 
Leandro Valiengo, PhD, Laboratory of Neurosciences (LIM-27), Institute of Psychiatry, of the Hospital 
das Clínicas of the University of São Paulo, R.Dr. Ovídio Pires de Campos, 785, 2° andar, Ala Sul, São 
Paulo (SP) 05403-903, Brazil (valiengo@usp.br) 

ABSTRACT 
 
 
Background: Recurrent transcranial magnetic stimulation (rTMS) is a consolidated procedure for the 
treatment of depression, with several meta-analyses demonstrating its efficacy. The theta burst 
stimulation (TBS) method is a modification of the usual rTMS protocol, with short bursts of stimulation 
at high frequencies, with the bursts themselves being applied 5 times per second. As a new intervention 
method, there are still few studies evaluating its efficacy in treatment of major depression. However, a 
recently published meta-analysis has pointed to benefits of this therapeutic modality. To date, there are 
no studies published with this method for the treatment of geriatric depression. 
Methods/design: The proposed study is designed as a double-blind clinical trial to assess the efficacy 
of rTMS theta-burst in the treatment of major depressive disorder in the elderly, in a sample of 108 
individuals. Patients will be randomized to two groups: the experimental (TBS) and comparative (sham) 
group. Inclusion criteria include a diagnosis of Major Depressive Episode and a minimum age of 60 
years. The coil will be positioned in the dorsolateral prefrontal cortex, with intermittent TBS mode on 
the left and continuous TBS on the right. There will be 20 consecutive sessions. Outcome measures will 
be at eight occasions: before the intervention (baseline) and after 1, 2, 4, 6, 8 and 12 weeks of onset. 
The main clinical result will be measured using the Hamilton Depression Scale (HDRS), comparing the 
initial scores with those obtained at the end of 6 weeks after the intervention. As secondary outcomes, 
we will use the Global Clinical Impression Scale (CGI), the CIRS (Cumulative Disease Assessment 
Scale), the Geriatric Depression Scale (GDS), the intermediate scores obtained on the HDRS scale and 
the variations in serum BDNF concentrations. As parameters of tolerability and safety, the incidence of 
adverse events and the occurrence of manic and / or hypomanic symptoms will also be assessed by the 
Young Mania Scale (YMRS). 
EXPECTED RESULTS: TBS stimulation will prove to be a safe, well-tolerated and effective 
intervention for the treatment of major depression in the elderly, becoming a more therapeutic option, 
particularly useful for patients with poor response or contraindications to the use of antidepressants. 
Trial registration: NCT0484292 Registered on https://clinicaltrials.gov/ct2/show/NCT04842929 
 
KEYWORDS: depression; major depressive disorder; elderly; antidepressant; Repetitive transcranial 
magnetic stimulation (rTMS), theta-burst (TBS). 

Introduction 
 
 
With the increase in life expectancy and, consequently, the proportion of elderly people in the 
population, the morbidity of this age group will be increasingly relevant in terms of public health. As in 
other age groups, major depressive disorder (MDD) is a major problem for the elderly. Several studies 
demonstrate that MDD also worsens the prognosis of cardiovascular and cerebrovascular diseases, the 
main causes of morbidity and mortality in the elderly. For example, it is known that MDD, besides being 
an independent risk factor for cardiovascular disease 1,2,3,4, it is also associated with other risk factors 
such as arterial hypertension 5,6, diabetes mellitus 7 and smoking 8,9. In addition, clinical trials in patients 
with cardiovascular diseases have demonstrated that antidepressant use decreases mortality 10,while the 
severity and persistence of depression in patients who had acute myocardial infarction increased 
mortality over subsequent years 11. Finally, the presence of MDD is also associated with decreased 
cognitive and functional capacity 12. In this way, the treatment of depression in the geriatric population 
is important not only from the psychiatric point of view, but also clinical and functional. 
The treatment of choice for geriatric unipolar depression is with antidepressants. The 
therapeutic response is considered to be similar to adult depression, remission rates that stabilize at 60- 
70% after more than three antidepressant treatments, and therefore approximately 30% of patients are 
resistant to pharmacological interventions13. However, there are not many clinical trials focusing 
specifically on the elderly population - in fact, much of the evidence for elderly antidepressant drug 
therapy is extrapolated from adult clinical trials or post-hoc analyses of these trials, focusing on the 
elderly subgroup14. Interestingly, a clinical trial that recruited only patients over 75 years did not 
demonstrate superior efficacy of citalopram over placebo in the treatment of depression15. Still in the 
pharmacotherapy of geriatric depression, important issues are the side effects, drug interactions and 
restrictions of use of antidepressants in this age group. For example, the elderly are more sensitive to 
anticholinergic effects (constipation, urinary retention) characteristic of tricyclic antidepressants and the 
noradrenergic (dry mouth, tremor) effects of "dual inhibitors"16. Medications for therapeutic potentiation 
of antidepressants also have important side effects, such as lithium (intoxication by decreasing renal 
clearance, dehydration) and antipsychotics (weight gain, extrapyramidal symptoms) 16. For these 
reasons, the therapeutic adherence to pharmacological treatment for depression in this age group is 
usually low 17. Among the biological treatments, we highlight electroconvulsive therapy (ECT) and 
repetitive transcranial magnetic stimulation (rTMS). Both are treatments approved for depression and 
effective in the geriatric age group 18,19, however they have some issues that limit their use. ECT is 
associated in some cases with cognitive deficits in the long term and its application requires sedation - 
in fact, ECT is usually reserved only for cases of severe, refractory and / or psychotic depression 20. 
The rTMS is a consolidated treatment for depression, with several meta-analyses demonstrating 
its efficacy 21,22. However, there are few studies that have specifically evaluated the efficacy of rTMS 
in the geriatric population 23-27. The rTMS may have some advantages over medications for the 
treatment of MDD in the elderly population. First, rTMS offers few 

side effects, with headache being the most common complaint28. The most serious adverse event is a 
seizure; however, using the safety parameters, it is an extremely rare event, with few reports of cases in 
the literature29. Additionally, the risk of drug interaction observed with the use of antidepressants and 
other medications of continuous use is null, a situation very common among depressed elderly people. 
Also, rTMS does not negatively interfere with patients' cognitive function, and may even improve it in 
some aspects30. Theta burst stimulation (TBS) is a method of rTMS that more closely mimics the natural 
rhythms of activity in the neurons of the brain and uses short bursts of stimulation at high frequencies, 
with the bursts themselves being applied 5 times per second31. Its main advantage against conventional 
rTMS is the shorter time of section (3 to 12 minutes, against 20-30). One non inferiority trial showed 
the same efficacy of the conventional rTMS32. No controlled studies with TBS have been performed in 
the treatment of geriatric depression; however, recent studies with the method have shown good 
prospects for the treatment of major depression in adults with meta-analyses demonstrating a possible 
clinical superiority over conventional rTMS 33-38. In addition, the session time in which the patient stays 
in the machine during TBS is much shorter, which facilitates patient compliance. 
We want to evaluate if TBS is a therapeutically effective alternative, and also with few side 
effects, for this geriatric population with depression. This may bring short-term clinical gains for 
depressed elderly patients who do not tolerate antidepressants or have been refractory to antidepressants. 
Methods/design 
Design and population 
 
The study will be a randomized, double-blind, sham-controlled clinical trial in which volunteers 
will be recruited at the Clinical Hospital of the Medical School of University of São Paulo. They will be 
allocated to one of the groups: active TBS or sham stimulation. Participants will receive 20 consecutive 
work days of TBS and will return at the end of 4, 6, 8 and 12 weeks for one single session, evaluation 
of clinical outcomes. Those who do not present clinical improvement and have been allocated to the 
sham group may choose to receive 20 days of active stimulation after the end of the trial. 
 
Randomization and allocation of participants 
 
The randomization will be in block, in which there will be permutation in the order and size of 
the blocks. The randomization will be generated through the website www.randomization.com by a 
researcher who will not be directly linked to the research. Patient allocation will be done through sealed, 
opaque and standardized envelopes. After the patient signs the informed consent form, the envelope will 
be opened and the envelope will be allocated to the treatment, in a coded form. The envelope will be 
identified with a random number that will be assigned to each patient. 

Inclusion and exclusion criteria 
 
Patients older than 60 years, with initial HDRS greater than 17, who have MDD. The exclusion 
criteria will be: other mental disorders (alcohol or drug addiction, psychotic disorders, dementia, bipolar 
disorder); presence of serious neurological or clinical diseases; presence of severe suicidal ideation and 
CIRS (Cumulative Illness Rating Scale) score> 7, characterizing a set of clinical morbidities that could 
impair adherence to the research protocol. In addition, specific contraindications to the use of rTMS will 
also be excluded, such as: metal implants, epilepsy or electronics in the cephalic segment. Patients who 
are receiving antidepressants will have a wash-out of five half-lives of the medications prior to entry 
into the study. Patients receiving benzodiazepines will be included since receiving a maximum dose of 
10mg of diazepam or equivalent. Other psychoactive drugs will be accepted as long as the doses of the 
medications have been stable for at least 6 weeks. 
 
Blinding 
 
The study will be double-blind, evaluators and patients will not be aware of the randomized 
treatment until the end of the study. The blinding will be done with a sham coil, which consists of a coil 
that reproduces the sound that the true coil does, but without generating the magnetic field. A person 
only intended to apply the rTMS session will do the procedure and will not be involved with the 
evaluations or with the evaluators, this person will be also blinded. A blinding scale will be applied to 
evaluators, applicators, and volunteers to evaluate if the blinding was effective. 
 
Interventions 
 
The coil will be positioned in the prefrontal dorsolateral cortex, with intermittent TBS (TBSi) 
mode on the left and continuous TBS (TBSc) on the right (F3 and F4 positions determined by the 10– 
20 Electroencephalographic International System). 1800 pulses will be used on each side, totaling 11 
minutes 39 seconds of total duration. TBS will have the following parameters: in cTBS bursts of three 
pulses at 50 Hz (20-ms interval between stimuli) will be applied continuously for 120 s total in the right 
DLPFC and iTBS bursts of three pulses at 50 Hz (20-ms interval between stimuli) will be applied for 2- 
s duration repeated every 10 s for a total time of 570 s also totaling 1800 pulses in the left DLPFC, both 
with 120% of motor threshold. We will use a magnetic stimulator device (MagVenture©) in study mode 
for double-blind trials. The coil has a side that is active and the other is sham. The applicant of TMS 
will be blinded too (after placing the coil over the patient's head and entering his number, the device 
tells if the position is correct or if you have to turn it, but the applicant does not know externally what 
is the sham side of the coil). The sham produces the same sound as the real one. We also put on the head 
electrodes that give stimulus to mimic the real magnetic coil (both groups receive this). There will be 

20 consecutive sessions, one per day, except on weekends and holidays, totaling around 4 weeks. A day 
of stimulation with the same technique will be done in the 6th week, 8th week and 12th week. 
 
Clinical variables 
 
We will use the MINI questionnaire for the diagnosis of psychiatric disorders, applied by an 
experienced psychiatrist. It is translated and validated into the Portuguese language39. The demographic 
and clinical profile of the patients will be evaluated by: gender, age, schooling, socioeconomic status, 
clinical comorbidities, use and dose of antidepressants and other psychoactive drugs. 
The main outcome will be measured using the HDRS scale. The primary evaluation will be done 
at the end of 6 weeks from the start of the first day of TBS. As secondary outcomes we will use the 
GDS (Geriatric Depression Scale), Cumulative Illness Rating Scale (CIRS), the global clinical 
impression scale (CGI), Positive and Negative Affect Scale (PANAS), Montgomery-Asberg 
Depression Rating Scale (MADRS), and Edinburgh Handedness Inventory (EHI). All scales have 
already been translated and validated into Portuguese40. Outcomes will be measured on 7 occasions: 
baseline after 1, 2, 4, 6, 8 and 12 weeks of study entry. The presence of adverse effects and the Young 
mania (YMRS) questionnaire will also be evaluated to detect manic and / or hypomanic cycling. 
 
Cognitive Assessments 
 
The cognitive battery will be applied by experienced neuropsychologists. For cognitive 
assessments they will be exploratory, secondary outcomes will be measured on the baseline, on the 20th 
day of the session and the addenbrooke cognitive examination will also be reapplied on the 12th week. 
We will use the Addenbrooke’s Cognitive Examination - Revised Version (ACE-R), Ravlt - Word List, 
Rey's complex figure, Stroop Test (violet version); Wais III - Subtest Codes; Trail Making A and B and 
WASI - Vocabulary and Matrix Reasoning subtest. 
 
Biomarkers 
 
BDNF (brain-derived neurotrophic factor) is implicated in the pathophysiology of depression. 
Recent meta-analyses have shown that depressed patients have lower serum levels of BDNF than normal 
subjects 41,42. The samples will be collected in dry tubes, centrifuged within two hours after collection, 
then separate the serum and refrigerate it in eppendorfs at -70oC in liquid nitrogen. The samples will 
therefore be stored in a cryogenic bank. They will be collected at the beginning of the study and in the 
6th week. 
Cerebrospinal fluid (CSF) samples will be collected by means of a lumbar puncture during the 
evaluation procedures before the intervention begins. They will be used for the investigation of beta- 
amyloid peptide (Aβ1-42) and Tau protein (total and phosphorylated). These determinations will allow 

the analysis of the interaction between the presence of Alzheimer's disease pathology and the therapeutic 
response to the TBS intervention. 
Cortical excitability will be measured using an EMT device with a circular coil, positioned at 
45º from the skull, in M1. This procedure will involve the application of a magnetic pulse generated by 
the EMT device, on the surface of the skull corresponding to the hand area of the right and left primary 
motor cortex. A surface electromyograph will be placed in the region of the abductor pollicis brevis 
muscle to measure the motor response of the hand. 
Evaluation of sensitivity thresholds according to the Quantitative Sensitivity Test (TQS): This 
assessment is made by the psychophysical method that quantifies the positive and negative phenomena 
of exteroceptive sensitivity transmitted by the thin or thick fibers of the peripheral nervous system. It 
makes it possible to determine the thresholds for detecting general sensitivities and pain, and generates 
painful stimuli that make it possible to diagnose the occurrence of hyperalgesia or hyperpathy. The TQS 
device was developed by Fruhstorfer et al. (1976) and Dyck et al. (1978), in order to quantify the 
sensitivity exams in clinical practice. At the beginning of the test, the stimulator temperature (thermode) 
is maintained in the thermal adaptation range (31 (C to 36˚C). The perception of the hot or cold stimulus 
and the pain of hot or cold stimuli is determined by increasing or decreasing the temperature of the 
thermometer. The cutaneous receptors, that is, the free nerve endings, which, in turn, trigger action 
potentials in the thin myelinated A-delta and / or unmyelinated C fibers, which are transmitted to the 
long tracts of the spinal cord. 
Diffuse Nociceptive Inhibitory Control (CIND) or Conditioned Pain Modulation (MCD) 
CIND is a term used to demonstrate a reduction in pain, in response to the application of painful 
stimuli outside the area of pain. In general, heterotopic painful stimuli tend to decrease the pain 
induced by harmful stimulation, applied extra-segmentally. Studies show that the application of 
harmful heat to a part of the body, such as the arm, ends up resulting in a decreased response to stimuli 
painful in a heterotopic region, using the legs as an example. CIND was developed and formulated 
describing a specific inhibitory mechanism mediated by the brain stem. Researches based on human 
beings, using a pain that inhibits other pain, admitted to adopting the term CIND, extending it to the 
psychophysical domain, and describing patterns of behavior that may belong to various neural 
mechanisms. The volunteers will be submitted to the same test stimulus: heat pain evoked by a 
suprathreshold stimulus with a thermode (30x30, Medoc) for five seconds on the thigh, on the right 
and left leg, with a maximum temperature of 49 ° C. The thermode is placed on the right thigh and then 
on the left thigh of the volunteer, instructed to press the mouse button when the temperature reached 
causes the onset of a hot pain. To verify the supra-painful stimulus, the temperature found as the LdorQ 
of the volunteer and the previous LdorQ is added by 2 ° C, in the Medoc machine we select the 
suprathreshold stimulus and set it so that the stimulus lasts 5s, and is at a temperature of 2 ° above the 
LdorQ , the volunteer is then invited to describe his pain to the respective stimulus with a VAS scale> 
70/100 mm, if the VAS reported by the volunteer is less than 70, we repeat the stimulus gradually 
increasing the temperature by 1 in 1 ° C, until he reports a VAS of at least 70/100 

millimeters. The tests will be done before starting the TBS sessions and in the 4th week. 
Actigraphy consists of a wrist device equipped with an accelerometer, a microprocessor and an 
internal memory, which are capable of detecting and storing the movement record. It is used in the 
evaluation of sleep disorders such as diseases of circadian rhythm, insomnia and excessive daytime 
sleepiness. We will use the actigraphy on the left wrist of the volunteers 1 week before the beginning of 
the research and for another 4 weeks after the studyThe objective is to assess sleep changes associated 
with the clinical response to magnetic stimulation. 
Pupil Examination (PLR) the participant will do a test lasting about 20 minutes in which a 
camera phone will record the size of your pupil during this period while you will hear some sounds. The 
exam is painless and without side effects. 
 
Sample size calculation: 
 
Based on the clinical trial of Li43, which demonstrated an efficacy favoring bilateral TBS in 
depression of 52.5% for the active group and 17.4% for the sham group, for a two-tailed p 0.05 and a 
power of 90%, the total sample size Is 86 subjects. Considering a rate of friction of approximately 25%, 
we estimated the final sample size in 108 patients. 
 
Statistical analysis 
 
Statistical analysis will be performed with the Stata 16 SE program for Mac OS X. All analyzes 
will be made on the intention to treat principle (ie the data of all participants will be included in the 
analysis) in which lost data will be allocated according to the last observation carried forward principle 
and/or mixed data. Analyzes will be considered significant at p <0.05. We will use parametric tests to 
analyze the main outcomes, which are allowed by the sample size. Number of previous admissions, 
presence of clinical comorbidities, refractoriness (measured by the Massachusetts General Hospital 
scale - MGH-S)44 will be analyzed as ordinal data. For the main outcome we will use a repeated measures 
analysis, having HDRS scores as Dependent variable and TBS as independent variable at week 8. 
Secondary analyses of the other scales and biomarkers will be performed in the same way, replacing 
HDRS as a dependent variable. 
 
Study Flow Chart 
 
We show below the flowchart for each patient throughout the study. It is worth remembering 
that TBS will be applied 23 times: 20 consecutive sessions (week 0 through week 4), 6th week, 8th week 
and 12th week. Still, patients who receive sham stimulation and who are still depressed may receive 
active stimulation at the end of the study. 

Table 1. Study schedule 
 
Triage 
Baseline 
Week 
1 
2 
3 
4 
6 
8 
12 
Assessment of 
eligibility 
X 
Structured interview 
(MINI) 
X 
Consent form 
X 
Theta-burst stimulation 
(active/sham) 
D 
D 
D 
D 
W 
W 
W 
Clinical interviews 
X 
X 
X 
X 
X 
X 
X 
Adverse effects 
X 
X 
X 
X 
X 
X 
Blood collection for 
serum biomarkers 
X 
X 
Neuropsychological 
evaluation 
X 
X 
X 
Cerebrospinal fluid 
collection 
X 
“D” and “W” represent interventions performed daily and weekly, respectively. 
 
 
Ethical aspects and safety 
 
The rTMS is very safe when used properly and has few adverse effects, and as mentioned above, 
the most common is headache. Applications will always be made in a hospital setting with a physician 
present. We will evaluate patients 23 times over 12 weeks - so that we can quickly identify any 
worsening of the clinical picture and perform early intervention. 
The study is approved by the Research Ethics Committee (CAAE: 80215117.5.0000.0068). 
All enrolled subjects will consent to participate through an Informed Consent Form.All the 
procedures described present minimal risk. If a volunteer presents a risk of major suicide, the same will 
be excluded from the study, adopting the standard procedure for the management of this type of patient. 
Participants may have access to their data and may leave the study at any time, without prejudice to 
any treatment they may perform within the institution. The data will be collected, analyzed and 
published in order to preserve the anonymity of the individual. In addition, the study will be 
conducted in accordance with all requirements of the Research Ethics Committee and also based on 
the recommendations established in the Declaration of Helsinki (1964), as amended in Tokyo (1975), 
Venice (1983) and Hong Kong (1989). As a benefit, participants will be able to participate in a clinical 
trial to treat their clinical condition. This 

will be possible even if they receive sham stimulation, as they may receive active stimulation at the end 
of the study if they still have severe depressive symptoms. 
Discussion 
 
Here we provided the study protocol of a randomized controlled trial (RCT) that will evaluate 
the efficacy of TBS for the treatment of geriatric depression. To the best of our knowledge, this is the 
first study in this field. The participants will receive 23 sessions of bilateral TBS, comprising first 
inhibitory stimulation delivered by cTBS in the right DLPFC followed by excitatory stimulation 
delivered by iTBS in the left DLPFC, totalizing 3600 pulses. We performed sample size calculation 
based on the effect size found in the most similar clinical trial found in literature 45. There are no specific 
treatments using neuromodulation for depression in the elderly. This study aims to answer this question. 
We will enroll patients with different degrees of refractoriness and the TBS as the only treatment for 
depression (the antidepressants will be wash-outed). , which will significantly increase the external 
validity of our results. These data could contribute to the analysis of some predictors of response as well. 
We expect that TBS will be statistically superior to sham treatment for depression as assessed 
through the Hamilton Depression Rating Scale (HDRS). Other expected secondary outcomes consist of: 
TBS will be superior to sham treatment for improvement of depressive symptoms by the GDS (Geriatric 
Depression Scale), the MADRS (Montgomery-Asberg Depression Rating Scale), and the Global 
Clinical Impression Print Scale (CGI). Regarding serum markers, we expect that the TBS group active 
vs. sham will show a significant increase in BDNF levels. From the neurocognitive point of view, we 
expect that both groups will perform similarly. 
Conclusions 
 
This study will investigate the efficacy of TBS for the treatment of major depressive disorder in 
elderly patients using a randomized, sham-controlled design. The biomarker investigation will 
contribute to the understanding of the neurobiological mechanisms of depression and their relationship 
with the treatment. This trial will contribute valuable information to the treatment of depression in the 
elderly. 
 
 
Author´s contributions: 
 
 
LV is responsible for initiating and managing the trial, conceived and designed the essay, 
analyse the data and wrote the manuscript. PJCS, WG, AB, OF performed the statistical analyzes, LS, 
RB, CM, JL are responsible for the clinical evaluation.LT, HC, RV, RM responsible for the 
neuropsychological evaluation. PO responsible for the collection of CSF, KM responsible for collecting 

cortical excitability,CIND andMCD. BP, BT responsible for collecting Pupil Examination.. VS is 
responsible for the application of rTMS. All authors contributed, read and approved the final manuscript. 
Funding 
 
This study Supported by a NARSAD Young Investigator Grant from the Brain & Behavior 
Research Foundation (grant number 19/28755). 
 
 
Conflicts of Interest 
 
 
The remaining authors declare that the research was conducted in the absence of any commercial 
or financial relationships that could be construed as a potential conflict of interest 
 
 
Acknowledgements 
 
 
We thank for supporting this study both the Coordenação de Aperfeiçoamento de Pessoal de 
Nível Superior (CAPES) for the financial support provided to Instituto Nacional de Biomarcadores em 
Neuropsiquiatria (INBioN) and also the NARSAD Young Investigator Grant. 
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