Depression-Reduction by Accelerated Personalized NeuroModulation and Its Effects on Sleep

Study Overview
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Brief Summary
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Advances in repetitive transcranial magnetic stimulation (rTMS) protocols with intermittent theta-burst stimulation (iTBS) have significantly decreased the duration for one single session and thereby enabled accelerated treatment plans with multiple sessions per day, potentially reducing the total treatment duration. This randomized, placebo-controlled study investigates the effects of accelerated iTBS treatment with connectivity-informed neuronavigation on symptom severity, sleep, interoception, and cognitive control in patients with major depressive disorder and with or without comorbid borderline personality disorder using magnetic resonance imaging (MRI).

Detailed Description
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Repetitive transcranial magnetic stimulation (rTMS) is a safe and efficacious treatment option for treatment-resistant depression. Advances in rTMS protocols with intermittent theta-burst stimulation (iTBS) have significantly decreased the duration for one single session and thereby enabled accelerated treatment plans with multiple sessions per day, potentially reducing the total treatment duration. Major depressive disorder (MDD) is characterized by impairments in various domains including sleep, impulse control, and interoception. Borderline personality disorder (BPD) is characterized by fear of abandonment, mood swings, and an unstable perception of self and often occurs with comorbid MDD. This comorbidity frequently impedes treatment of the BPD. In this randomized, placebo-controlled study, 60 patients with treatment-resistant MDD (30 verum group, 30 sham group) and 60 patients with treatment-resistant MDD and comorbid BPD (30 verum group, 30 sham group) will receive two weeks of connectivity-informed iTBS of the left dorsolateral prefrontal cortex (DLPFC; 3 sessions per day, 5 days per week). Before and after the treatment phase, (functional) magnetic resonance imaging (fMRI) will be performed. The effects of iTBS will be tested in four domains: (1) symptom severity (MDD and BPD symptoms), (2) sleep quality (sleep questionnaires and various sleep parameters monitored via an electroencephalography (EEG) headband), (3) neurocognitive effects (vigilance and response inhibition measured with behavioral and fMRI tasks), and (4) interoception (interoceptive attention measured with behavioral and fMRI tasks). Furthermore, before the start of the two-weeks treatment, a single iTBS session (forecaster session) will be conducted to explore the validity of early symptom/mood responses and hormonal changes for the prediction of the the treatment outcome. Treatment effects will be analyzed within and across patient groups (MDD and MDD + BPD). In addition, domain-specific treatment effects will be analyzed as a function of distinct iTBS targets within the DLPFC.To evaluate pathological biases, the investigators will compare the patients' data with a control group of 30 healthy participants who will also be tested twice (without iTBS).

Official Title
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Depression-Reduction by Accelerated Personalized NeuroModulation and Its Effects on Sleep

Conditions
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Major Depressive Episode, Major Depressive Disorder, Borderline Personality Disorder

Intervention / Treatment
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* Device: intermittent theta burst stimulation (iTBS) or sham stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is able to provide consent. Diagnosis of major depressive disorder (MDD) according to DSM-V criteria. During the current episode, treatment-resistant MDD (at least one failed pharmacological trial of adequate dose and duration) For the MDD group with comorbid borderline personality disorder (BPD): diagnosis of BPD according to the Diagnotic Statistical Manual V (DSM-V) criteria. For healthy controls: no psychiatric or neurological illness. Exclusion Criteria: For the MDD group without BPD: BPD diagnosis The participant does not fulfill requirements for iTBS treatment according to safety guidelines. The participant does not fulfill requirements for MRI measurements according to safety guidelines. Pregnancy or breast-feeding. Acute suicidality. Neurological illness (e.g. dementia, Parkinson's disease, chorea huntington, multiple sclerosis). increased current risk for epileptic seizure. comorbid diagnosis of schizophrenia or psychotic symptoms, bipolar disorder, and substance use disorder within the last 6 months. Conditions related to increased intracranial pressure. Brain injury or stroke.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Major Depressive Episode<br>At least one failed pharmaco trial in current episode | Device: intermittent theta burst stimulation (iTBS) or sham stimulation<br>* 30 sessions of iTBS over 2 weeks (3 sessions per day, 5 days per week)<br>|
| Major Depressive Episode with comorbid Borderline Personality Disorder<br>At least one failed pharmaco trial in current episode | Device: intermittent theta burst stimulation (iTBS) or sham stimulation<br>* 30 sessions of iTBS over 2 weeks (3 sessions per day, 5 days per week)<br>|
| Healthy Controls<br>No psychiatric disorders | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in depression severity after the treatment phase | Measured with the Montgomery Asberg Rating Scale (MARDS). Remission defined as MADRS score (range: 0 to 60) of less than or equal to 10. Response defined as a reduction of at least 50 percent from baseline in MADRS score. | Up to 5 weekdays after the last iTBS treatment session | 
| Change in BPD severity after the treatment phase | Measured by the Zanarini rating scale for BPD (Zan-BPD, range 0-36). Remission is defined as score of 9 or less. Response defined as a decrease from baseline in Zan-BPD score of at least 20 percent of the scoring range, i.e. a reduction of 8 points or more. | Up to 5 weekdays after the last iTBS treatment session | 
| Changes in neural responses in an interoception task before the first and after the last treatment session | Measured with functional magnetic resonance imaging (fMRI) while performing an interoception task | Up to 5 weekdays before the first and after the last treatment session | 
| Changes in neural responses in a cognitive control task before the first and after the last treatment session | Measured with functional magnetic resonance imaging (fMRI) while performing a cognitive control task | Up to 5 weekdays before the first and after the last treatment session | 
| Changes in behavioral responses in an interoception task before the first and after the last treatment session | Measured as performance in an interoception task during fMRI | Up to 5 weekdays before the first and after the last treatment session | 
| Changes in behavioral responses in a cognitive control task before the first and after the last treatment session | Measured as performance in a cognitive control task during fMRI | Up to 5 weekdays before the first and after the last treatment session | 
| Changes in sleep staging over the treatment course | electroencephalography (EEG)-based sleep staging measured with a headband device with accelerometer and pulseoximeter | 2 days of baseline measurement before the first iTBS session, daily over the treatment course for 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in brain connectivity measures | Structural and functional connectivity measured with MRI including graph measures | Up to 5 weekdays before the first and after the last treatment session | 
| Changes in vigilance over the treatment course | Vigilance measured by Psychomotor Vigilance Task (PVT) | Baseline immediately before the first iTBS session, daily over the treatment course for 10 days | 
| Changes in symptom severity over treatment course | Measured by the MADRS | Baseline immediately before the first iTBS session, after 1 week of treatment, after 2 weeks of treatment, and at the follow-up 6 weeks after treatment | 
| Changes in self-reported symptom severity over treatment course and at follow-up | measured by the Beck Depression Inventory (BDI-II) | Baseline immediately before the first iTBS session, daily over the treatment course for 10 days, 6 weeks after last iTBS session at the follow-up | 
| Changes in Cortisol Awakening Response (CAR) from saliva concentrations | 3 measurements after awakening (0,20, and 40 minutes) | Up to 5 weekdays before the first and after the last treatment session | 
| Changes in blood parameters | Pro- and anti-inflammatory cytokines, and growth factors | Before the first and after the last treatment session | 
| Association between changes induced by the Forecaster session and treatment outcome | Changes in biomarkers before and after the forecaster iTBS session | Immediately before and after the forecaster iTBS session | 
| Changes in self-reported BPD symptom severity over treatment course and at follow-up | Measured by the Borderline Symptom List (BSL-23) (range 0-4) | Baseline immediately before the first iTBS session, daily over the treatment course for 10 days, 6 weeks after last iTBS session at follow-up | 
| Changes in BPD symptom severity over treatment course and at follow-up | Measured by Zan-BPD | Baseline immediately before the first iTBS session, after 1 week of treatment, and after 2 weeks of treatment | 
| Changes in food craving | Measured by a behavioral food craving task | Up to 5 weekdays before the first and after the last treatment session | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rTMS, Theta Burst Stimulation, Neuronavigation, Major Depressive Episode, Borderline Personality Disorder, Sleep, Interoception, Cognitive Control, fMRI