Transcranial Magnetic Stimulation (TMS) therapy is an approved and effective treatment option in treatment-resistant depression. The present study aims to investigate the effect of TMS treatment on microvasculature stracture of the retina and the choroid. These patients will be evaluated using the Optical Coherence Tomography Angiography (OCTA) device, which is quick and non-invasive, and provides volumetric data with the clinical capability of specifically localizing and delineating pathology along with the ability to show both structural and blood flow information in tandem. The main question it aims to answer is:

• Does TMS treatment influence the retinal vasculature ? The patients will visit the ophthalmology clinic before and after the TMS treatment.
• TMS treatment will be applied 5 days a week for 4 weeks.

This prospective cohort study aims to investigate the impact of transcranial magnetic stimulation (TMS) on retinal microvasculature of the retina and the choroid in patients with treatment resistant depression (TRD). TRD represents a subset of major depressive disorder where patients do not adequately respond to conventional antidepressant treatments. Emerging evidence suggests that TMS, a non invasive brain stimulation technique, can effectively alleviate symptoms in TRD patients. However, the implications of TMS on ocular health, particularly the retina, remain poorly understood. This study seeks to fill this knowledge gap by assessing retinal vasculature before and after a structured TMS treatment protocol.

The study will enroll 30 patients diagnosed with TRD according to The Diagnostic and Statistical Manual of Mental Illnesses (DSM-5) criteria. Participants will undergo a TMS treatment regimen using the MagVenture™ MagProX100™ device. The treatment protocol includes 20 sessions over four weeks, delivering 18,000 pulses in total. The stimulation targets the left dorsolateral prefrontal cortex, with parameters set to achieve optimal therapeutic effects without inducing adverse side effects. Motor threshold measurements will be conducted prior to the initiation of treatment and adjusted weekly to maintain consistent treatment intensity. The control group will be consisted of 30 healthy participants. They will not be treated nor followed, they just will be evaluated for ophthalmologic measurements for once.

Comprehensive ophthalmologic examinations will be performed on all patients both before and after the completion of the TMS treatment. These examinations will include assessments of retinal vasculature using OCTA). Psychiatric assessments using the the Patient Health Questionnaire (PHQ-9) and Hamilton Depression Rating Scale (Ham17) will be conducted to evaluate changes in the severity of depressive symptoms.

The primary objective is to determine whether TMS therapy induces changes in microvasculature of the retina and the choroid in TRD patients. Secondary objectives include evaluating the safety and tolerability of TMS in this population, assessing changes in depressive symptomatology, and examining potential interactions between TMS and concurrent antidepressant use. Primary outcomes will focus on changes in retinal vasculature pre- and post TMS treatment. Secondary outcomes will assess the clinical response to TMS based on standard psychiatric scales, record any TMS-related side effects, and explore associations between treatment effects and antidepressant use.

Inclusion Criteria:

• Diagnosed with Major Depressive Disorder according to DSM-5 TR.
• Lack of response to treatment after being administered at least two different antidepressants and anti-obsessive agents at effective doses and durations.
• The clinical condition cannot be better explained by a metabolic or organic disorder.
• Routine electroencephalography (EEG) findings before TMS do not indicate electrical activity consistent with an epileptic focus.
• Routine blood tests before TMS show no conditions that could affect treatment levels, particularly thyroid issues, vitamin deficiencies, or inflammation parameters that might cause depression or cognitive impairment (consultation with relevant departments if necessary).
• No history of hearing loss identified during routine evaluations (if a history of hearing loss exists, consultation will be requested; if none, the process will proceed accordingly).

Exclusion Criteria:

• According to the pre-TMS risk assessment form, there is a contraindication for treatment,
• Epileptic focus is detected in the pre-TMS electroencephalography findings,
• Previous head trauma, loss of consciousness and intra-cerebral surgery,
• A metal particle caused by an aneurysm clip, connection tongs or explosive substances that will affect the electromagnetic field in the brain,
• A significant disorder in the thyroid hormone profile in routine blood checks before TMS,
• A significant increase in inflammation markers in routine checks before TMS,
• A vitamin deficiency that may cause cognitive impairment or forgetfulness in routine blood checks before TMS,
• A presence of electrolyte imbalance in routine blood checks before TMS,
• The patient has previously had a psychotic attack or bipolar mood attack,
• The patient has previously had a substance-induced psychosis or bipolar mood disorder,
• The patient has previously used substances known as alcohol, drugs or stimulants according to DSM-V TR and semi-structured clinical interview (SCID-5 TR) have abuse or addiction (except if they have not used in the last 12 months or have not abused alcohol),
• Those who want to terminate TMS treatment voluntarily,
• If an unexpected clinical situation occurs during TMS treatment, the patient will be excluded from the study.

Individual Participant Data (IDP) will be shared together with the Clinical Study Report

Supporting Information:

• Study Protocol
• Informed Consent Form (ICF)
• Clinical Study Report (CSR)

The data will be made available immediately after the publication, and will remain available for at least 5 years.

Anyone who wishes to access the data