Translational Biomarkers in Accelerated Neuromodulation for Treatment-resistant Depression

Developing Translational Biomarkers to Predict Clinical Response in Treatment-resistant Depression: Towards a Personalized, Plasticity-enhancing Accelerated Neuromodulation

Background: 30-50% of patients with Major Depressive Disorder (MDD) do not respond adequately despite two or more antidepressant treatments with proper dosage and timing of administration, configuring a condition of Treatment-Resistant Depression (TRD). Repetitive Transcranial Magnetic Stimulation (rTMS) is a neuromodulation technique that uses a magnetic field to stimulate focal cortical brain regions and it has been approved by the FDA for the treatment of TRD. Accelerated rTMS (arTMS) protocols involve multiple daily sessions of rTMS and they have been shown to be equally effective and safe compared to rTMS protocols, with reduced administration time and potentially faster antidepressant efficacy.

Objectives: The main aim of this study is to identify MDD endophenotypes/biotypes predictive of response to accelerated treatment of rTMS to better characterize the clinical correlates of response in patients with TRD.

Eligibility: Subjects between 18 and 65 years suffering from TRD in stable psychopharmacological treatment for at least one month.

Design: This clinical trial includes three phases: 1) a screening phase; a rTMS continued treatment phase; and a follow-up.

In order to be enrolled, participants will be screened with:

• Medical history to assess the existence of the inclusion criteria and exclude any medical conditions that could contraindicate treatment with arTMS
• Questionnaires

After being enrolled, baseline data will be collected. In particular, participants will be administered:

• Questionnaires
• Functional MRI
• Cognitive tasks
• Eye examination with Electroretinography (ERG)
• Blood sampling
• Salivary cortisol sampling

Repetitive TMS will be delivered during 5 outpatient treatment days (4 times/die).

After treatment patients will be contacted by telephone on a weekly basis for the first 3 weeks, to carry out an assessment of the clinical condition.

A follow-up visit, in the clinic, will be carried out after 21 days from the last stimulation (Friday), with the administration of psychometric scales.

Blood samples will be taken on the first day of stimulation and the day after the last stimulation.

Salivary cortisol sampling will be taken before the start of the stimulation protocol, after the first stimulation day and immediately after the last stimulation session foreseen by the protocol.

fMRI will be performed during baseline and at the end of treatment. ERG will be performed before the start of the stimulation protocol, after the first stimulation and immediately after the last stimulation session foreseen by the protocol. Patients will undergo ERG again during the follow-up visit at 21 days.

Treatment includes:

• rTMS: A brief electrical current passes through the coil placed on the head. At each day, participants will receive four rTMS sessions (36 min), with a 55 min interval between sessions.
• MRIs: Patients will undergo two MRI sessions lasting 45 min. Blood pressure and respiratory rate will be recorded before the examination. During fMRI, patients will be asked to perform tasks.
• Eye examination with Electroretinography (ERG)
• Blood and salivary sampling.
• Screening tests and questionnaires.

The main aim of the study is to identify MDD endophenotypes/biotypes predictive of response to accelerated treatment of rTMS to consolidate the use of a cost-effective protocol and to better characterize the clinical correlates of response in patients with TRD. In addition, the present study proposes the following secondary objectives: A) identification of applicable and reliable peripheral biomarkers related to endophenotypes/biotypes, exportable in clinical practice to predict response to treatment; B) evaluation of potential synergistic, additive or antagonistic effects of MDD pharmacotherapies when used in combination with neuromodulation interventions.The study includes 3 psychiatric assessments with psychometric testing: T0 (enrollment), T1 (day 6), T2 (week 3, follow-up). At T0 (enrollment) the Researcher will fully inform the patient about the study, obtaining the patient's informed consent to participate in the study, and will determine the patient's eligibility. Patients will also undergo a battery of cognitive tasks aimed at measuring any changes caused by the neuromodulatory action of arTMS. During T1 (day 6), and T2 (3 weeks) the patient will again undergo the tests and neurocognitive evaluations. arTMS protocol involves 20 rTMS sessions (4/daily for 5 consecutive days, each session lasts 35 min with an interval of 55 min). Coil is placed on the left dorsolateral prefrontal cortex (LDLPFC), trains have a frequency of 10 Hz and a intensity of 120% of the individual resting motor threshold.

To investigate the possible effects of arTMS on brain connectivity, patients will undergo a functional neuroimaging study based on fMRI on T0 and T1. MDD biomarkers measurable by ERG could represent a valid aid in the personalization of treatments. ERG will be performed before the start of the stimulation protocol (T0), after the first stimulation and immediately after the last stimulation session foreseen by the protocol. Patients will undergo ERG again during the follow-up visit at 21 days (T2). Blood samples will be taken on the first day of stimulation (T0) and the day after the last stimulation to identify reliable peripheral biomarkers related to endophenotypes/biotypes, exportable in clinical practice to predict response to treatment. Salivary cortisol sampling will be taken before the start of the stimulation protocol (T0), after the first stimulation day and immediately after the last stimulation session foreseen by the protocol. Some variations in neuroendocrine biomarkers such as cortisol seem to be predictive of response to arTMS treatment. The analysis of the neuroimaging, ERG and peripheral data will lead to identify MDD endophenotypes/biotypes predictive of response to accelerated treatment of arTMS.

Inclusion Criteria:

• Current diagnosis of Major Depressive Disorder (MDD), based on the Diagnostic and Statistical Manual of Mental Disorder - Fifth Edition (DSM-5);
• Subjects without clinical response to at least two antidepressant treatments administered at adequate dosage and duration during the current episode;
• Stable psychopharmacological treatment for at least one month.

Exclusion Criteria:

• Co-morbidity with organic diseases that could interfere with magnetic stimulation safety (epilepsy, brain lesions or diseases, previous neurosurgery, metal grafts, cardiac devices) based on applied procedure guidelines;
• Diagnosis of Substance or Alcohol Use Disorder (DSM-5) in the past 6 months;
• Substances of abuse or alcohol acute intoxication or abstinence;
• Co-morbidity with significant organic or neurological diseases;
• Personal or familiar (1st degree relatives) medical history of seizures;
• Significant eye diseases that could interfere with ERG execution;
• For female patients: Pregnancy/breastfeeding.