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| Name | Class |
|---|---|
| Marc Onken, M.Sc. | UNKNOWN |
| Christina Mueller, M.Sc. | UNKNOWN |
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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).
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Major Depressive Episode | At least one failed pharmaco trial in current episode |
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| Major Depressive Episode with comorbid Borderline Personality Disorder | At least one failed pharmaco trial in current episode |
| |
| Healthy Controls | No psychiatric disorders |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| intermittent theta burst stimulation (iTBS) or sham stimulation | Device | 30 sessions of iTBS over 2 weeks (3 sessions per day, 5 days per week) |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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Patients at the Department of Psychiatry, University of Oldenburg. The patients' diagnosis of MDD and BPD will be verified via the structured clinical interview for DSM-V. Healthy controls will be matched to the patient sample.
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| Name | Affiliation | Role |
|---|---|---|
| René Hurlemann, Prof. | Department of Psychiatry, University of Oldenburg | Principal Investigator |
| Dirk Scheele, Dr. | Department of Psychiatry, University of Oldenburg | Principal Investigator |
| Christina Mueller, M.Sc. | Department of Psychiatry, University of Oldenburg | Study Director |
| Marc Onken, M.Sc. | Department of Psychiatry, University of Oldenburg | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Psychiatry, University of Oldenburg | Bad Zwischenahn | 26160 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29726344 | Background | Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018 Apr 28;391(10131):1683-1692. doi: 10.1016/S0140-6736(18)30295-2. Epub 2018 Apr 26. | |
| 19170404 |
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| ID | Term |
|---|---|
| D003865 | Depressive Disorder, Major |
| D001883 | Borderline Personality Disorder |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D010554 | Personality Disorders |
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Blood samples without DNA analysis Saliva samples without DNA analysis
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 |
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 |
| Background |
| Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Dialogues Clin Neurosci. 2008;10(4):473-81. |
| 30917990 | Background | Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019 Mar 27;364:l1079. doi: 10.1136/bmj.l1079. |
| 24168753 | Background | Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014 Jul;44(10):2029-40. doi: 10.1017/S0033291713002535. Epub 2013 Oct 29. |
| 16259539 | Background | Tsuno N, Besset A, Ritchie K. Sleep and depression. J Clin Psychiatry. 2005 Oct;66(10):1254-69. doi: 10.4088/jcp.v66n1008. |