Transcranial Electrical Stimulation for Comorbid Depression and Chronic Pain
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18-80
SponsorShanghai Mental Health Center
About this trial
The goal of this clinical trial is to learn if active transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) can improve pain symptoms in patients with major depressive disorder (MDD) and chronic pain symptoms. It will also explore the neural mechanisms underlying these potential effects. The main questions it aims to answer are:
1. Are there any differences in the overall efficacy among the three intervention groups (tACS, tDCS, and sham)? 2. Is active tACS superior to sham stimulation in reducing pain symptoms in patients with MDD and chronic pain over the 2-week treatment period and at the 6-week follow-up? 3. Is active tACS superior to active tDCS in reducing pain symptoms? 4. Does active tACS, compared to tDCS, demonstrate a more persistent improvement in pain symptoms, as measured at the 6-week follow-up? 5. As an exploratory objective, what neural oscillation entrainment mechanisms underlie the potential analgesic effects of tACS?
Researchers will compare three parallel groups: active tACS, active tDCS, and sham stimulation, to evaluate their efficacy. All three groups are randomized and double-blinded.
In addition, a separate exploratory open-label cohort of 10 participants will receive the same active tACS intervention while performing a cognitive task. This exploratory arm is designed to investigate the neural oscillation entrainment effects of tACS. Data from this arm will be analyzed separately and are not included in the primary confirmatory analyses.
Participants in the main randomized trial will:
1. Receive 40 minutes of stimulation (tACS, tDCS, or sham) once daily, 5 days per week, for 2 weeks (10 sessions total). 2. Complete clinical assessments and cognitive tests at baseline, mid-intervention (week 1), post-intervention (week 2), and at a 6-week follow-up. 3. Undergo resting-state functional MRI (rs-fMRI) and blood sample collection at baseline and post-intervention for exploratory biomarker analyses.
Participants in the exploratory open-label arm will:
1. Receive active tACS (1 mA, 10 Hz, 40 minutes) once daily, 5 days per week, for 2 weeks (10 sessions total), while performing a cognitive task during stimulation. 2. Complete resting-state and task-state EEG recordings at the following time points:
(1) At baseline (pre-intervention) (2) Immediately before and after the 1st tACS session (3) Immediately before and after the 10th tACS session (4) On the day after completion of all 10 sessions These EEG recordings are designed to assess: (1) the immediate entrainment effects of a single tACS session, (2) the cumulative effects after repeated tACS sessions, and (3) the persistent neural plasticity changes following the full intervention course.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Meets the diagnostic criteria for a depressive episode (DSM-5);
HAMD-17 score of ≥8 and ≤23 (mild-to-moderate depressive symptoms) based on the current assessment;
4 or higher on Item 5 of the Brief Pain Inventory (BPI), and persistent pain lasting more than three months;
Ages 18-80;
Disqualifiers
Diagnosed according to the DSM-5 as meeting any of the following criteria: ① Major depressive disorder or treatment-resistant depression (HAMD-17 score ≥ 24, and the current episode has lasted ≥ 2 years, or the current episode has been unresponsive to treatment with ≥ 2 antidepressants); ② Schizophrenia spectrum disorder; ③ Bipolar I disorder; ④ Anxiety disorders (including generalized anxiety disorder, panic disorder, social anxiety disorder, etc.); ⑤ Depressive disorder caused by a medical condition.
Experiencing malignant pain caused by cancer pain syndrome, visceral pain (such as stomach pain), referred pain (such as back pain caused by pancreatitis), and so on;
Patients with severe or unstable physical illnesses, including but not limited to: neurological disorders (such as epilepsy, stroke, migraine, history of cranial surgery, etc.); neurological disorders accompanied by structural brain abnormalities (e.g., traumatic brain injury, recent stroke, brain tumor); cardiovascular diseases (e.g., uncontrolled hypertension, heart failure, arrhythmias, myocardial infarction, etc.); respiratory diseases (e.g., severe sleep apnea syndrome); malignant tumors or immunodeficiency; uncontrolled diabetes (fasting blood glucose > 12 mmol/L);
Excessive alcohol consumption within 30 days prior to the start of the trial, or a history of alcohol or drug dependence within the past 6 months;
Trial design
Design model
Parallel
Treatments tested in this trial
tDCS
DeviceParticipants receive active tDCS. The anodal electrode (5 × 5 cm) is placed over the left dorsolateral prefrontal cortex (F3), and the cathodal electrode (5 × 7 cm) is placed over the right dorsolateral prefrontal cortex (F4). A constant current of 2 mA is applied for 40 minutes per session, with a 30-second ramp-up and ramp-down period. The intervention is administered once daily for 2 weeks (total of 10 sessions).
alpha-tACS
DeviceParticipants receive active alpha-tACS. Two electrodes are placed over F3 and F4. A sinusoidal alternating current at 10 Hz frequency (alpha band) is applied 1 mA (zero-to-peak) at the F3 and F4 electrodes. Stimulation duration is 40 minutes per session, including 30-second ramp-up and ramp-down periods. The intervention is administered once daily, 5 days per week, for 2 weeks (total of 10 sessions).
Sham
DeviceSham group using the same electrode montage at F3/F4. To maintain blinding, the stimulator delivers current only during the initial 30-second ramp-up period, followed by an immediate ramp-down, and a final 30-second ramp-up at the end of the stimulation session. This mimics the initial sensation of active stimulation without delivering sufficient current to induce neural modulation.
Treatment groups
160 Participants
are divided into 4 treatment groupsGroup A: tDCSExperimental treatment 1 intervention
Group B: alpha-tACSExperimental treatment 1 intervention
Group C: ShamSham comparator 1 intervention
Group D: Exploratory Open-Label tACS GroupExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Proportion of Participants Achieving MCID on BPI Pain Intensity Subscale
Description: The BPI is a validated self-administered questionnaire that assesses the severity of pain and its impact on daily functioning. The pain intensity subscale consists of four items rating pain at its "worst," "least," "average," and "current" (right now). Each item is rated on a 0 to 10 numeric rating scale. Higher scores mean a worse outcome. The Minimal Clinically Important Difference (MCID) is defined as a reduction of ≥ 1 point from baseline in the BPI pain intensity score. The outcome is the proportion of participants in each group who achieve this MCID threshold at each follow-up time point.
Time frame
At 1 week (mid-intervention), 2 weeks (end of intervention), and 6 weeks (follow-up) post-baselineSecondary outcomes
1
Percentage Reduction from Baseline in HAMD-17 Total Score
The HAMD-17 is a 17-item clinician-rated scale assessing depression severity. Items are rated on 3- or 5-point scales, with total scores ranging from 0 to 52. Higher scores mean a worse outcome (greater depression severity). The outcome is the percentage reduction in HAMD-17 total score from baseline at each follow-up time point, calculated using the formula: \[(Baseline score - Follow-up score) / Baseline score\] × 100% A positive percentage indicates improvement (reduction in depressive symptoms).
Time frame
At 1 week (mid-intervention), 2 weeks (end of intervention), and 6 weeks (follow-up) post-baseline2
Change from Baseline in HAMD-17 Total Score
The Hamilton Depression Rating Scale (HAMD-17) is a 17-item clinician-rated scale assessing depression severity. Items are rated on 3- or 5-point scales, with total scores ranging from 0 to 52. Higher scores indicate greater depression severity (worse outcome). The outcome is the absolute change in the total score from baseline at each follow-up time point, calculated as: \[(Baseline score) - (Follow-up score)\]. A positive change value indicates improvement (reduction in depressive symptoms). No pre-defined clinically meaningful threshold is applied to this continuous outcome; it is reported as the mean absolute change per group.
Time frame
At 1 week (mid-intervention), 2 weeks (post-intervention), and 6 weeks (follow-up)3
Change from Baseline in Pain Catastrophizing Scale (PCS) Total Score
The Pain Catastrophizing Scale (PCS) is a 13-item self-reported questionnaire. Each item is rated on a 5-point Likert scale from 0 (not at all) to 4 (all the time), with total scores ranging from 0 to 52. Higher scores indicate higher levels of pain catastrophizing (worse outcome). The outcome is the absolute change in the total score from baseline at each follow-up time point, calculated as: \[(Baseline score) - (Follow-up score)\]. A positive change value indicates improvement (reduction in pain catastrophizing).
Time frame
At 1 week (mid-intervention), 2 weeks (end of intervention), and 6 weeks (follow-up) post-baseline4
Change from Baseline in Generalized Anxiety Disorder Scale-7 (GAD-7) Total Score
The GAD-7 is a 7-item self-report scale (0-21, higher scores = worse outcome) assessing anxiety symptoms over the past two weeks. The outcome is the absolute change in the total score from baseline at each follow-up time point, calculated as: \[(Baseline score) - (Follow-up score)\].
Time frame
At 1 week (mid-intervention), 2 weeks (end of intervention), and 6 weeks (follow-up) post-baselineOther outcomes
1
Change from Baseline in Brain-Derived Exosome Metabolite Levels
Metabolite profiles are measured using untargeted liquid chromatography-mass spectrometry (LC-MS) in plasma-derived brain-enriched exosomes. Changes in metabolite profiles from baseline to post-intervention are assessed using multivariate partial least squares discriminant analysis (PLS-DA). The primary comparison is the separation distance (e.g., Q² or R² values) between baseline and post-intervention clusters, with positive values indicating greater separation between the two time points. This is an exploratory outcome to identify potential metabolic biomarkers and generate hypotheses related to the mechanisms of tACS/tDCS action. Results will be reported descriptively and are not part of the primary confirmatory analysis.
Time frame
From baseline to post-intervention at 2 weeks2
Change from Baseline in BPI Pain Intensity Score in the Exploratory Open-Label Cohort
This exploratory outcome measures the change from baseline in the BPI Pain Intensity score after 10 sessions of active tACS in the open-label arm. Data are reported descriptively as individual change values, mean change, standard deviation, and within-group effect size (Cohen's d) . No formal hypothesis testing is planned; the results will inform effect size estimation for future trial planning.
Time frame
From baseline to post-intervention at 2 weeks3
Change from Baseline in HAMD-17 Total Score in the Exploratory Open-Label Cohort
This exploratory outcome measures the change from baseline in HAMD-17 total score after 10 sessions of active tACS in the open-label arm. Data are reported descriptively as individual change values, mean change, standard deviation, and within-group effect size (Cohen's d). No formal hypothesis testing is planned; the results will inform effect size estimation for future trial planning.
Time frame
From baseline to post-intervention at 2 weeks4
Change from Baseline in GAD-7 Total Score in the Exploratory Open-Label Cohort
This exploratory outcome measures the change from baseline in GAD-7 total score after 10 sessions of active tACS in the open-label arm. Data are reported descriptively as individual change values, mean change, standard deviation, and within-group effect size (Cohen's d). No formal hypothesis testing is planned. GAD-7 scores will also be explored as a covariate in pain outcome analyses.
Time frame
From baseline to post-intervention at 2 weeksSponsors and contacts
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Shanghai Mental Health Center
Lead sponsor
Shanghai 10th People's Hospital
Collaborator
Shanghai Tongji Hospital, Tongji University School of Medicine
Collaborator
Source ClinicalTrials.gov