Translational Biomarkers in Accelerated Neuromodulation for Treatment-resistant Depression

Condition(s) studied

Investigational drug(s) / intervention(s)

Accelerated Repetitive Transcranial Magnetic Stimulation: rTMS is a non-invasive brain stimulation technique. It will be used a MagPro R30 with the Cool-B-70 figure-of-eight coil (MagVenture, Falun, Denmark).

Study summary

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.

Eligibility

Primary outcome measure(s)

• Changes in psychometric test indicator of depression - MADRS — Baseline; each 1 day of treatment ; at 1, 2, 3 and 4 weeks.
  Montgomery Asberg Depression rating scale (MADRS - 10 items - score 0-60) to measure relevance of mood, concentration, physical and sleep symptoms
• Changes in psychometric test indicator of depression - HAM-D 21 — Baseline; 1 week; 4 weeks
  Hamilton Depression Scale (HAM-D - 21 items - score 0-69) to assess relevance and pervasiveness of depressive symptoms
• Changes in neuroplasticity - structural RM and fMRI (physiological parameter) — Baseline; day 6
  Functional MRI (which requires a preliminary structural MRI) produces images of the brain both in a "resting state" and when it is engaged in producing movements, sensations or when concentrated in activities involving emotional and cognitive responses. It is based on the ability to capture the signals emitted by hydrogen atoms when they are subjected to a magnetic field.
• Changes in neuroplasticity - DTI (physiological parameter) — Baseline; day 6
  Diffusion Tensor Imaging (DTI) techniques to assess the integrity of white matter tracts between brain regions. DTI data, accompanied by fMRI studies, in subjects with MDD are indicative of reduced functional connectivity between cortical and subcortical structures. It is based on the principle of Brownian motion of water molecules, the signal is directly proportional to the integrity of the myelin sheath.
• Changes in responsivity of nervous tissue (physiological parameter) — Baseline; 4 weeks
  ERG will be performed to gain an easy access to structural and functional nervous tissue alterations, usually observed in MDD patients and partially reversible with antidepressant treatment. The ERGs records the electrical activity following single light stimuli (flash), able to provide an indication of the activity of the external (cones, rods) and intermediate (amacrine, bipolar cells) layers of the retina
• Rate of genetic polymorphism predictor of treatment response — Baseline; day 6
  Genetic tests investigating polymorphism (5-HT2A, 5-HT1A and BDNF receptors), possible predictors of antidepressant treatment response
• Change in BDNF level (physiological parameter) — Baseline; day 6
  BDNF levels will be evaluated by collecting a venous blood sample. BDNF is a member of the nerve growth factor (NGF) family of neurotrophic growth factors. Low levels of peripheral BDNF and NGF have been reported in mood disorders and other psychopathological conditions with normalization after antidepressant treatment or mood stabilization. The increase in serum levels of BDNF seems to reflect the concomitant activation of BDNF synthesis that accompanies the neuronal remodeling triggered by the suspension of alcohol intake and suggests that the synthesis of BDNF may have a role in the long-term maintenance of alcohol abstention. BDNF measurements will be calculated in pg/ml
• Change in pro-BDNF (physiological parameter) — Baseline; day 6
  Pro-BDNF is the precursor of BDNF and it acts as a repository of mature BDNF and acts itself by inducing neuronal thinning. Pro-BDNF levels will be evaluated by collecting a venous blood sample. Pro-BDNF measurements will be calculated in ng/ml.
• Changes in peripheral biomarkers - HPA axis (blood) — Baseline; day 6
  Hypothalamic-Pituitary-Adrenal axis will be evaluated assessing blood cortisol (mcg/dL) and ACTH (mcg/dL) levels
• Changes in peripheral biomarkers - HPT axis (FT3/FT4) — Baseline; day 6
  Hypothalamic-Pituitary-Thyroid aill be evaluated assessing, FT3 (pmol/L) and FT4 ( pmol/L) levels
• Changes in peripheral biomarkers - HPT axis (TSH) — Baseline; day 6
  Hypothalamic-Pituitary-Thyroid aill be evaluated assessing TSH (μIU/mL)
• Changes in peripheral biomarkers - HPA axis (saliva) — Baseline; day 6
  Hypothalamic-Pituitary-Adrenal axis will be evaluated assessing salivary (µL) levels of cortisol
• Changes in peripheral biomarkers - C reactive protein (physiological parameter) — Baseline; day 6
  C reactive protein, that indicates the inflammation degree, in mesured in mg/L.

Trial sites (1)

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