Transcranial Electrical Stimulation for Comorbid Depression and Chronic Pain

Shanghai Mental Health Center160 enrolled

Overview

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.

Study Type

Interventions

tDCSDEVICE

Participants 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-tACSDEVICE

Participants 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).

ShamDEVICE

Sham 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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Meets the diagnostic criteria for a depressive episode (DSM-5); 2. HAMD-17 score of ≥8 and ≤23 (mild-to-moderate depressive symptoms) based on the current assessment; 3. 4 or higher on Item 5 of the Brief Pain Inventory (BPI), and persistent pain lasting more than three months; 4. Ages 18-80; 5. Right-handed, with normal hearing, vision, or corrected vision; 6. Have a high school education or higher and be able to understand and complete research-related assessments; 7. Maintain a consistent regimen of analgesic and antidepressant medications and psychotherapy (including dosage and type of medication or treatment method) for four weeks prior to enrollment; 8. The subject (or his or her legal representative, if applicable) signed an informed consent form stating that he or she understood the purpose and procedure of the trial and was willing to participate in it. Exclusion Criteria: 1. 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. 2. 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; 3. 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); 4. 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; 5. Women who are pregnant, breastfeeding, or planning to become pregnant within 3 months of the start of the trial; 6. Currently taking medications that affect cortical excitability (e.g., benzodiazepines, antiepileptic drugs); 7. Have undergone neurostimulation therapy within the past 3 months, including electroconvulsive therapy (MECT), repetitive transcranial magnetic stimulation (rTMS), or transcranial electrical stimulation (tES); 8. Suffers from claustrophobia and is unable to undergo an fMRI scan (applies to subjects who require a functional MRI scan); 9. Contraindications to transcranial electrical stimulation (such as intracranial metal implants, pacemakers, cochlear implants, skin abrasions at the stimulation site, or a personal or family history of epilepsy, etc.); 10. Currently participating in another clinical trial, has participated in a clinical trial within the past 90 days, or plans to participate in another clinical trial during the study; 11. Participants with obvious suicidal tendencies, impulsive behavior, or an inability to cooperate with study evaluators; 12. Accompanied by psychotic symptoms; 13. Researchers believe there are other circumstances that make a participant unsuitable for the trial; 14. Patients with severe cognitive impairment (MMSE ≤ 17) were excluded; 15. Participants who are unable to cooperate with the study; 16. Those who voluntarily withdrew midway.

Outcomes

Primary Outcomes

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-baseline

Secondary Outcomes

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-baseline

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)

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-baseline

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-baseline

Change from Baseline in Clinical Global Impression (CGI) Total Score

The Clinical Global Impression (CGI) scale consists of two clinician-rated subscales assessing overall treatment response: CGI-Severity (CGI-S): Rates the severity of the patient's illness on a 7-point scale from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Higher scores mean a worse outcome. CGI-Improvement (CGI-I): Rates the patient's improvement compared to baseline on a 7-point scale from 1 (very much improved) to 7 (very much worse). This subscale is only assessed at post-baseline time points. Lower scores mean a better outcome (greater improvement). The outcome is the change from baseline in CGI-S score at each follow-up time point, and the CGI-I score at each post-baseline time point.

Time frame: At 1 week (mid-intervention), 2 weeks (post-intervention), and 6 weeks (follow-up)

Change from Baseline in Resting-State Functional Connectivity of the DLPFC at 2 Weeks

Resting-state functional connectivity (rs-FC) of the dorsolateral prefrontal cortex (DLPFC) is assessed using resting-state functional magnetic resonance imaging (rs-fMRI). The primary measurement is the change in seed-based functional connectivity strength between the DLPFC and its target network regions (e.g., parietal cortex, default mode network nodes), quantified as Fisher-transformed correlation coefficients (z-values) from a priori defined regions of interest. Higher z-values indicate stronger positive functional connectivity; lower or negative values indicate weaker or anticorrelated connectivity. Structural MRI (sMRI) is acquired for co-registration and normalization purposes.

Time frame: Baseline and immediately after the 2-week intervention period

Transcranial Electrical Stimulation for Comorbid Depression and Chronic Pain

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts