Pain and Major Depressive Disorder
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|ClinicalTrials.gov Identifier: NCT04556890|
Recruitment Status : Not yet recruiting
First Posted : September 21, 2020
Last Update Posted : September 21, 2020
|Condition or disease||Intervention/treatment||Phase|
|Major Depressive Disorder Chronic Pain||Device: Active rTMS/Active iTBS DFPLC/Sham Pain M1 Device: Sham rTMS/ Active iTBS Pain Device: Active rTMS/Active iTBS||Not Applicable|
The main objective of the proposed study is to evaluate the therapeutic effect of multi-site repetitive Transcranial Magnetic Stimulation (rTMS) on chronic pain and inflammatory responses in Major Depressive Disorder (MDD). MDD is the leading cause of disability worldwide. One reason for the extraordinarily high burden of depression is painful somatic symptoms: more than half of MDD patients complain of moderate to severe pain that is associated with interference in function and unemployment and which can lead to opioid use disorder. The neuro-immune interaction is increasingly understood as the underlying mechanism of this comorbidity. Sustained psychosocial stress can cause a lasting increase in systemic inflammation, which may be a key mediator of chronic pain and depression. Pro-inflammatory cytokines have been linked to the dysregulation of signaling in the mesocorticolimbic system and affect-related circuits present in both chronic pain and depression. Meta-analyses have identified higher CRP, IL6, and TNFa among depressed patients. Additionally, CRP was found to be increasingly higher with higher number failed treatment trials, suggesting that treatment resistant depression (TRD) patients who qualify for rTMS tend to have higher inflammation than those who respond to pharmacological antidepressant treatment . Further, baseline levels of transcriptional control pathways (TCP) related to immune or sympathetic activation and glucocorticoid insensitivity mediate experimentally induced depressed mood. Even though the inflammatory reaction may originate in the periphery, downstream effects can result in neuroinflammation and changes in neural network function through several immune-to-brain signaling pathways. Previous research has shown that functional connectivity between DLPFC and anterior cingulate cortex (ACC) also mediates neuroinflammation levels in ACC, and which was linked to depressive scores in chronic pain patients . rTMS to the left dorsolateral prefrontal cortex (DLPFC) is a non-invasive neuromodulation technique that has proven clinical efficacy for MDD and rTMS to primary motor cortex (M1) has been demonstrated to reduce chronic pain, including fibromyalgia, neuropathic pain, headache and regional pain].
Based on these findings, the investigators hypothesize that combined rTMS to depression and pain targets will reduce both depressive and pain symptoms and will also result in an effective reduction of systemic inflammation. The proposed research will examine the effects of 30 neuro-navigated sessions of active vs. sham rTMS using four conditions: A) active rTMS at DLPFC and sham at M1; B) active rTMS at M1 and sham at DLPFC; C) active rTMS at DLPFC and M1; D) sham rTMS at DLPFC and M1. This design will help to dissociate the impact of an antidepressant response on pain reduction (condition A), the analgesic effect on depressive symptoms (condition B), or whether the combined treatment (condition C) will result in a synergetic effect. The investigators will focus on pain types related to inflammation including fibromyalgia (FM) and ME/CFS, whose symptomatic profiles are closely overlapping with those of MDD and may thus preferentially respond to rTMS.
The investigators will combine the analysis of circulating pro-inflammatory cytokines with transcriptomic analyses, which may be even more sensitive to short-term changes. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) data will be used to assess biomarkers and mechanisms of action (MOA) of successful rTMS treatment for pain. The conceptualization of pain treatment in MDD at the brain network and systemic levels makes this study a highly innovative approach to neuropsychiatric research.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||69 participants|
|Intervention Model:||Crossover Assignment|
|Intervention Model Description:||
The study design includes three different stimulation protocols consisting each of 30 sessions:
A) Active rTMS treatment for depression (600 pulses of active intermittent theta burst (iTBS) administrated at 120% MT to the left DLPFC) and sham treatment for pain at M1; B) Sham rTMS for depression and active iTBS for pain (600 pulses of iTBS followed by 1500 pulses of 10 Hz rTMS, both at 120% MT); C) Active rTMS treatment for both, depression and pain (600 pulses of iTBS to left DLPFC followed by 600 iTBS + 1500 pulses of 10 Hz to M1);
|Masking:||Double (Participant, Outcomes Assessor)|
|Masking Description:||All stimulation procedures will be double-blinded, with clinicians, raters and patients blinded to the type of administered treatment using a designated sham coil.|
|Official Title:||Pilot Study: Randomized, Sham-controlled Transcranial Magnetic Stimulation for the Treatment of Pain in Major Depressive Disorder (MDD)|
|Estimated Study Start Date :||September 30, 2020|
|Estimated Primary Completion Date :||September 30, 2022|
|Estimated Study Completion Date :||September 30, 2022|
|Experimental: Active rTMS/Active iTBS DFPLC/Sham Pain M1||
Device: Active rTMS/Active iTBS DFPLC/Sham Pain M1
Active rTMS treatment for depression (600 pulses of active intermittent theta burst (iTBS) administrated at 120% MT to the left DLPFC) and sham treatment for pain at M1
|Experimental: Sham rTMS/ Active iTBS Pain||
Device: Sham rTMS/ Active iTBS Pain
Sham rTMS for depression and active iTBS for pain (600 pulses of iTBS followed by 1500 pulses of 10 Hz rTMS, both at 120% MT
|Experimental: Active rTMS/Active iTBS||
Device: Active rTMS/Active iTBS
Active rTMS treatment for both, depression and pain (600 pulses of iTBS to left DLPFC followed by 600 iTBS + 1500 pulses of 10 Hz to M1
- Percent change in depression scores [ Time Frame: Through study completion, an average of 6 weeks ]Inventory of Depressive symptoms- Self (IDS-SR) scores will be analyzed as the primary outcome measure. The IDS-SR is a 30-item scale that measures various symptoms of depression. Each item is scored between 0-4. Severity of depression is associated with a higher score with scores ranging from 0 to 84.
- Percent change in pain score [ Time Frame: Through study completion, an average of 6 weeks ]McGill Pain questionnaire (MPQ) will be analyzed as the secondary outcome. MPQ is a self-reporting measure of pain used for patients with a number of diagnoses. It assesses both quality and intensity of subjective pain and effectiveness of an intervention. Scoring ranges from 0 to 78. A higher score is associated with greater pain.
- Levels of inflammatory markers and transcription factors [ Time Frame: Through study completion, average of 6 weeks ]Specimen will be processed and compared based on levels of pro-inflammatory cytokines and transcription factors (TF) related to immune activation, sympathetic activation and glucocorticoid insensitivity
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04556890
|Contact: Nikita Vincecruz, BAfirstname.lastname@example.org|