The Neurobiological Fundaments of Depression and Its Relief Through Neurostimulation Treatments

Study Overview
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Brief Summary
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The study will apply state of the art radiology through advanced magnetic resonance imaging (MRI) techniques to investigate structural and functional brain effects of electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS).

Detailed Description
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As a multi-disciplinary collaboration, imaging findings will be correlated to psychiatric response parameters, neuropsychological functioning as well as neurochemical and genetic biomarkers that can elucidate the underlying mechanisms. The aim is to document both treatment effects and potential harmful effects of ECT and TMS Sample, three groups: ECT: n = 50 patients in a major depressive episode (bipolar and major depressive disorder) who have accepted treatment with ECT. TMS: n = 50 patients in a major depressive episode (bipolar and major depressive disorder) who have accepted treatment with TMS. HC: = 50 age and gender matched healthy volunteers not receiving ECT nor TMS. Observation time: six months, with the time points as specified below. ECT is typically given three times weekly, but exceptions may occur. Hence, time points are specified as the number of ECT treatments given rather than an exact number of days which will vary. Tp1: 2 hours before the first treatment session (day 1, baseline), Tp2: 2 hours after the first treatment session (day 1), Tp3: before the 7th ECT session and corresponding time point for TMS (  day 15), Tp4: 1-2 weeks after last treatment session (  day 30 - 50), Tp5: 6 months after treatment (  day 180), Healthy controls are only assessed at Tp1,2,4,5

Official Title
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The Neurobiological Fundaments of Depression and Its Relief Through Neurostimulation Treatments

Conditions
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Healthy, Major Depressive Disorder 1, Major Depressive Disorder

Intervention / Treatment
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* Device: Electroconvulsive therapy
* Device: rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECT: Patients (>18) referred to the center of ECT and accepted for treatment because of moderate and severe depression fulfilling the criteria for the following ICD-10 diagnosis: F 31.3 and F31.4; F32.1 and F32.2 and F32.3; F33.1 and F33.2 and F33.3. In addition, the symptom intensity must be verified by a MADRS score ≥ 25. There is no upper age for participation, however, the responsible clinician will consider if patients are eligible for inclusion (functioning, enabled to give informed consent). TMS: Patients (>18) referred to the center of TMS and accepted for treatment because of moderate and severe depression fulfilling the criteria for the following ICD-10 diagnosis: F 31.3 and F31.4; F32.1 and F32.2 and F32.3; F33.1 and F33.2 and F33.3. In addition, the symptom intensity must be verified by a MADRS score ≥ 25. There is no upper age for participation, however, the responsible clinician will consider if patients are eligible for inclusion (functioning, enabled to give informed consent). Healthy controls: Age and gender matched (to the patient groups). No history of psychiatric illness and no current depression. No contraindication for MRI scanning. Exclusion Criteria: ECT / TMS treatment within the last 12 months. Patients unable to give informed consent (according to the responsible clinician or ECT / TMS responsible). Patients who cannot participate in the MR scanning

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients, depression, ECT<br>Patients in major depressive episode undergoing ECT | Device: Electroconvulsive therapy<br>* Treatment with Electroconvulsive therapy<br>|
| Patients, depression, TMS<br>Patients in major depressive episode undergoing TMS | Device: rTMS<br>* repetitive Transcranial Magnetic Stimulation<br>|
| Healthy<br>Healthy controls who do not receive ECT nor TMS but otherwise the same assessments. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cerebral Blood Flow from baseline | Estimated by Arterial Spin Labeling MRI | Baseline, day1 (after 1 ECT),   day 15 (after 6 ECTs),   day 30 - 50 (1-2 weeks after last ECT),   day 180 (6 months after treatment) | 
| Change in MADRS from baseline | Depression rating by MADRS score | Baseline, day1 (after 1 ECT),   day 15 (after 6 ECTs),   day 30 - 50 (1-2 weeks after last ECT),   day 180 (6 months after treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change fraction of in Isotropic hindered water | Measured by Restriction spectrum imaging. Increase in the fraction of isotropic hindered water as a sign of oedema / disruptive effects of ECT seen on Imaging at 2 hours after first ECT. | Baseline, day1 (after 1 ECT),   day 15 (after 6 ECTs),   day 30 - 50 (1-2 weeks after last ECT),   day 180 (6 months after treatment) | 
| Change in concentration of NAA, Choline, myo Inositol | MR Spectroscopy og the amygdala, measures of neuronal integrity. | Baseline, day1 (after 1 ECT),   day 15 (after 6 ECTs),   day 30 - 50 (1-2 weeks after last ECT),   day 180 (6 months after treatment) | 
| Changes in structural MRI T1 and T2 and RSI | Measures of brain structure | Baseline, day1 (after 1 ECT),   day 15 (after 6 ECTs),   day 30 - 50 (1-2 weeks after last ECT),   day 180 (6 months after treatment) | 
| Changes in functional MRI | Resting state MRI, measurement of functional connectivity | Baseline, day1 (after 1 ECT),   day 15 (after 6 ECTs),   day 30 - 50 (1-2 weeks after last ECT),   day 180 (6 months after treatment) | 
| Change in performance on test of spatial navigation | Neurocognitive assessments of spatial navigation | Baseline, day1 (after 1 ECT),   day 15 (after 6 ECTs),   day 30 - 50 (1-2 weeks after last ECT),   day 180 (6 months after treatment) |