Major Depressive Disorder
Conditions
Keywords
depression, transcutaneous spinal direct current stimulation, non-invasive, major depressive disorder
Brief summary
This pilot clinical trial will evaluate the efficacy and safety of transcutaneous direct current stimulation (tsDCS) in major depressive disorder.
Detailed description
This study aims to 1) determine the efficacy and safety of tsDCS in adult patients with major depressive disorder (MDD) and 2) investigate interoceptive awareness, somatic symptoms, autonomic and metabolic regulation as potential mediators of antidepressant response to tsDCS. We predict that 1) Active tsDCS treatment will result in a greater decrease in depressive symptom severity compared to Sham tsDCS in adult patients with MDD, 2) active tsDCS will be safe and well tolerated in adult patients with MDD and 3) change in interoceptive awareness, somatic symptoms, and autonomic and metabolic parameters will be associated with change in depressive symptom severity. To accomplish these aims, we will conduct an 8-week, double blinded, randomized, sham controlled, parallel group, pilot clinical trial study design. A total of 20 adult antidepressant-free MDD patients will be randomized to receive Active (n=10) or Sham (n=10) tsDCS protocols for 8 weeks in a 1:1 ratio. We will combine the use of a tsDCS device, psychometric instruments to diagnose MDD, and measures of depressive symptom severity, somatic symptoms, interoceptive awareness, autonomic function (blood pressure, heart rate), and potential metabolic markers as predictors of response.
Interventions
DEVICEActive transcutaneous spinal direct current stimulation
Active anode electrodes placed at Thoracic 10 level, Cathode electrode placed on right shoulder.
DEVICESham transcutaneous spinal direct current stimulation
Sham anode electrodes placed at Thoracic 10 level, Cathode electrode placed on right shoulder.
Sponsors
Lindner Center of HOPE
Brain & Behavior Research Foundation
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
An independent operator (trained personnel from the research team) will prepare the tsDCS device parameters for each session, but will not participate in the rest of the assessments. Patients and raters will remain blinded to spinal stimulation protocol assigned to each participant throughout the study.
Intervention model description
8-week, double blinded, randomized, sham controlled, parallel group, pilot clinical trial study design.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. age 18-55 yrs., inclusive 2. female or male 3. Body mass index (BMI) 18.5 to 35 kg/mts2, inclusive 4. current MDD episode diagnoses confirmed by Mini International Neuropsychiatric Interview (MINI) 5.0 with a duration of ≥1 month and ≤24 months 5. moderate MDD symptoms according to Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 20 to ≤35 6. no current or recent (past month) antidepressant pharmacological treatment 7. Generalized anxiety disorder (GAD) and other anxiety symptoms will be permitted 8. using an effective contraceptive method (all participants of childbearing potential).
Exclusion criteria
1. Current or lifetime MDD episode non-responsive to two or more antidepressant treatments at adequate doses and time (including ECT) 2. Current or lifetime bipolar disorder or schizophrenia diagnosis 3. current (past month): PTSD, psychotic or substance use disorder (nicotine and caffeine allowed) 4. significant risk of suicide according to Columbia Suicide Severity Rating Scale (CSSRS) or clinical judgment, or suicidal behavior in the past year 5. current chronic severe pain conditions 6. current chronic use of: opioids analgesics, medications that affect blood pressure or drugs with significant autonomic effects (stimulants and antipsychotics allowed if dose stable for 1 month) 7. neurological, endocrinological, cardiovascular (including diagnosed hypertension) or other clinically significant medical conditions as judged by the clinician 8. skin lesions on electrode placement region 9. implanted electrical medical devices 10. Pregnancy 11. suspected Intellectual quotient (IQ)\<80 12. any other clinically relevant reason as judged by the clinician.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery Asberg Depression Rating Scale (MADRS) Score Change | 8 weeks (or last available observation). | Difference in change from baseline to week 8 (or last available observation) in Montgomery Asberg Depression Rating Scale summed total scores scores between active and sham transcutaneous spinal direct current stimulation (tsDCS) groups. Scores range from 0 to 60, with higher scores indicating worse depressive symptom severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression-Improvement (CGI-I) | 8 weeks | Clinical Global Impression-Improvement (CGI-I) scale score at week 8 (or last available information) difference between Active and Sham tsDCS groups. Range is from 1 to 7 with lower scores indicating better outcome. |
| Montgomery Asberg Depression Rating Scale (MADRS) Sub-component Score (Item 2) Change | 8 weeks | MADRS Item 2 score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. MADRS Item 2 (Reported sadness) scores range from 0 to 6 and a higher score indicates a worse severity. |
| Patient Health Questionnaire-9 (PHQ-9) Score Change | 8 weeks | PHQ-9 score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Scores range from 0 to 27, with higher scores indicating worse severity. |
| Multidimensional Assessment of Interoceptive Awareness (MAIA) Score Change-Noticing Subscale | 8 weeks | MAIA Noticing subscale score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Noticing Subscale scores range 0 to 5 and higher scores indicate better outcomes. |
| Binge Eating Scale (BES) Score Change | 8 weeks | BES score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Scores range from 0 to 46, with higher scores indicating a worse outcome. |
| Four-Dimensional Symptom Questionnaire (4-DSQ)- Somatization Dimension Score Change | 8 weeks | 4-DSQ Somatization dimension score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Somatization scale scores range from 0 to 32, with higher scores indicating a worse outcome. |
| Systolic Blood Pressure Score Change | 8 weeks | Systolic Blood Pressure score change in mmHg from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Normal range is considered below 140 mmHg. A greater decrease from baseline to week 8 in mmHg is considered favorable. |
| Number of Participants With Skin Redness | 8 weeks | Number of participants with skin redness in the active and sham tsDCS groups. |
| Body Mass Index Change | 8 weeks | Body mass index (BMI) change in kg/mts2 from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Normal range is 18 to 25 kg/mt2. A decrease in value is considered favorable. |
| Adiponectin Level Change | 8 weeks | Adiponectin level change (in ug/mL) from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. No normative levels available. Decreased levels are considered favorable in the context of the study. |
| Leptin Level Change | 8 weeks | Leptin level (in ng/ml) change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Usual normal range 4.7 - 23.7 ng/ML. Decreased levels are considered favorable. |
| Cortisol Level Change | 8 weeks | Cortisol level change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Typical afternoon levels may range 5-10 nmol/L. Decreased levels are considered favorable outcomes. |
| Insulin Level Change | 8 weeks | Insulin level change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Fasting range typically 16-166 Milli-international Units Per Liter (mIU/L). Decreased levels are considered a favorable outcome. |
| Fibroblast Growth Factor-21 (FGF-21) Level Change | 8 weeks | Fibroblast growth factor-21 (FGF-21) level change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Levels in ng/ml. No normative range established. Decreased levels are considered favorable in the context of the study. |
| Fatty Acid (LCn-3) Level Change | 8 weeks | Fatty Acid (LCn-3) level percentage change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Results reported on Erythrocyte eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) percentage change. Increase in EPA+DHA would indicate a better outcome. |
| Heart Rate Score Change | 8 weeks | Heart Rate score change in beats per minute (BPM) from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Normal BPM is considered between 60 to 100. A decrease in value is considered favorable. |
Countries
United States
Participant flow
Recruitment details
All study procedures involving participants were conducted at the Lindner Center of HOPE (affiliated with the University of Cincinnati) in Mason, Ohio, with a recruitment period from August 29, 2018, to September 13, 2022.
Pre-assignment details
Pre-screened 671 participants. Forty two were assessed for eligibility on site. A total of 22 were excluded for not meeting eligibility criteria (n=19) or declined to participate (n=3). A total of 20 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Active Treatment Thoracic anodal transcutaneous spinal direct current stimulation 2.5 milliampere (mA) for 20 min/ three times per week for 8 weeks.
Active transcutaneous spinal direct current stimulation: Active anode electrodes placed at Thoracic 10 level, Cathode electrode placed on right shoulder. | 10 |
| Sham Treatment Thoracic anodal transcutaneous spinal direct current sham stimulation session of 20min/ three times per week for 8 weeks.
Sham transcutaneous spinal direct current stimulation: Sham anode electrodes placed at Thoracic 10 level, Cathode electrode placed on right shoulder. | 9 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Coronavirus disease (COVID-19) Pandemic Related Restrictions | 0 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Active Treatment | Sham Treatment | Total |
|---|---|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 9.8 | 36.8 years STANDARD_DEVIATION 13.1 | 34.2 years STANDARD_DEVIATION 11.45 |
| Montgomery Asberg Depression Rating Scale (MADRS) Score | 29.0 summed total scores STANDARD_DEVIATION 2.3 | 29.4 summed total scores STANDARD_DEVIATION 3.8 | 29.2 summed total scores STANDARD_DEVIATION 3.05 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 16 Participants |
| Region of Enrollment United States | 10 participants | 9 participants | 19 participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 10 / 10 | 9 / 9 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 |
Outcome results
Primary
Montgomery Asberg Depression Rating Scale (MADRS) Score Change
Difference in change from baseline to week 8 (or last available observation) in Montgomery Asberg Depression Rating Scale summed total scores scores between active and sham transcutaneous spinal direct current stimulation (tsDCS) groups. Scores range from 0 to 60, with higher scores indicating worse depressive symptom severity.
Time frame: 8 weeks (or last available observation).
Population: All participants with at least one post baseline Montgomery Asberg Depression Rating Scale total scores assessment were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Montgomery Asberg Depression Rating Scale (MADRS) Score Change | -21.7 summed total scores | Standard Error 2.3 |
| Sham Treatment | Montgomery Asberg Depression Rating Scale (MADRS) Score Change | -14.6 summed total scores | Standard Error 2.5 |
p-value: =0.04ANOVA
Secondary
Adiponectin Level Change
Adiponectin level change (in ug/mL) from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. No normative levels available. Decreased levels are considered favorable in the context of the study.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Adiponectin Level Change | -805 ug/mL | Standard Error 1640 |
| Sham Treatment | Adiponectin Level Change | 1472 ug/mL | Standard Error 2409 |
Secondary
Binge Eating Scale (BES) Score Change
BES score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Scores range from 0 to 46, with higher scores indicating a worse outcome.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Binge Eating Scale (BES) Score Change | -7.3 score on a scale | Standard Error 2.7 |
| Sham Treatment | Binge Eating Scale (BES) Score Change | -3.0 score on a scale | Standard Error 3 |
Secondary
Body Mass Index Change
Body mass index (BMI) change in kg/mts2 from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Normal range is 18 to 25 kg/mt2. A decrease in value is considered favorable.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Body Mass Index Change | -0.3 kg/m^2 | Standard Error 2 |
| Sham Treatment | Body Mass Index Change | 1.5 kg/m^2 | Standard Error 2.2 |
Secondary
Clinical Global Impression-Improvement (CGI-I)
Clinical Global Impression-Improvement (CGI-I) scale score at week 8 (or last available information) difference between Active and Sham tsDCS groups. Range is from 1 to 7 with lower scores indicating better outcome.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Clinical Global Impression-Improvement (CGI-I) | 1.3 total score of the scale | Standard Error 0.3 |
| Sham Treatment | Clinical Global Impression-Improvement (CGI-I) | 2.0 total score of the scale | Standard Error 0.3 |
Secondary
Cortisol Level Change
Cortisol level change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Typical afternoon levels may range 5-10 nmol/L. Decreased levels are considered favorable outcomes.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Cortisol Level Change | -0.7 nmol/L | Standard Error 2.2 |
| Sham Treatment | Cortisol Level Change | -0.9 nmol/L | Standard Error 3.1 |
Secondary
Fatty Acid (LCn-3) Level Change
Fatty Acid (LCn-3) level percentage change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Results reported on Erythrocyte eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) percentage change. Increase in EPA+DHA would indicate a better outcome.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Fatty Acid (LCn-3) Level Change | -0.02 Percentage change | Standard Error 0.19 |
| Sham Treatment | Fatty Acid (LCn-3) Level Change | -0.01 Percentage change | Standard Error 0.22 |
Secondary
Fibroblast Growth Factor-21 (FGF-21) Level Change
Fibroblast growth factor-21 (FGF-21) level change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Levels in ng/ml. No normative range established. Decreased levels are considered favorable in the context of the study.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Fibroblast Growth Factor-21 (FGF-21) Level Change | -13.3 ng/ml | Standard Error 53.2 |
| Sham Treatment | Fibroblast Growth Factor-21 (FGF-21) Level Change | -30.9 ng/ml | Standard Error 78.1 |
Secondary
Four-Dimensional Symptom Questionnaire (4-DSQ)- Somatization Dimension Score Change
4-DSQ Somatization dimension score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Somatization scale scores range from 0 to 32, with higher scores indicating a worse outcome.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Four-Dimensional Symptom Questionnaire (4-DSQ)- Somatization Dimension Score Change | -3.3 score on a scale | Standard Error 2.1 |
| Sham Treatment | Four-Dimensional Symptom Questionnaire (4-DSQ)- Somatization Dimension Score Change | -6.9 score on a scale | Standard Error 2.3 |
Secondary
Heart Rate Score Change
Heart Rate score change in beats per minute (BPM) from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Normal BPM is considered between 60 to 100. A decrease in value is considered favorable.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Heart Rate Score Change | 4.7 Beats per minute | Standard Error 3.9 |
| Sham Treatment | Heart Rate Score Change | 5.3 Beats per minute | Standard Error 4.2 |
Secondary
Insulin Level Change
Insulin level change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Fasting range typically 16-166 Milli-international Units Per Liter (mIU/L). Decreased levels are considered a favorable outcome.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Insulin Level Change | -4.2 Milli-international Units/ Liter (mIU/L) | Standard Error 4.6 |
| Sham Treatment | Insulin Level Change | -7.2 Milli-international Units/ Liter (mIU/L) | Standard Error 6.8 |
Secondary
Leptin Level Change
Leptin level (in ng/ml) change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Usual normal range 4.7 - 23.7 ng/ML. Decreased levels are considered favorable.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Leptin Level Change | -1.5 ng/mL | Standard Error 4.4 |
| Sham Treatment | Leptin Level Change | 2.7 ng/mL | Standard Error 6.4 |
Secondary
Montgomery Asberg Depression Rating Scale (MADRS) Sub-component Score (Item 2) Change
MADRS Item 2 score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. MADRS Item 2 (Reported sadness) scores range from 0 to 6 and a higher score indicates a worse severity.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Montgomery Asberg Depression Rating Scale (MADRS) Sub-component Score (Item 2) Change | -3.2 score on a scale | Standard Error 0.4 |
| Sham Treatment | Montgomery Asberg Depression Rating Scale (MADRS) Sub-component Score (Item 2) Change | -1.8 score on a scale | Standard Error 0.4 |
Secondary
Multidimensional Assessment of Interoceptive Awareness (MAIA) Score Change-Noticing Subscale
MAIA Noticing subscale score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Noticing Subscale scores range 0 to 5 and higher scores indicate better outcomes.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Multidimensional Assessment of Interoceptive Awareness (MAIA) Score Change-Noticing Subscale | -0.0 score on a scale | Standard Error 0.5 |
| Sham Treatment | Multidimensional Assessment of Interoceptive Awareness (MAIA) Score Change-Noticing Subscale | -0.2 score on a scale | Standard Error 0.5 |
Secondary
Number of Participants With Skin Redness
Number of participants with skin redness in the active and sham tsDCS groups.
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Treatment | Number of Participants With Skin Redness | 9 Participants |
| Sham Treatment | Number of Participants With Skin Redness | 4 Participants |
Secondary
Patient Health Questionnaire-9 (PHQ-9) Score Change
PHQ-9 score change from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Scores range from 0 to 27, with higher scores indicating worse severity.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Patient Health Questionnaire-9 (PHQ-9) Score Change | -12.6 score on a scale | Standard Error 2.2 |
| Sham Treatment | Patient Health Questionnaire-9 (PHQ-9) Score Change | -10.3 score on a scale | Standard Error 2.4 |
Secondary
Systolic Blood Pressure Score Change
Systolic Blood Pressure score change in mmHg from baseline to week 8 (or last available observation) difference between Active and Sham tsDCS groups. Normal range is considered below 140 mmHg. A greater decrease from baseline to week 8 in mmHg is considered favorable.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment | Systolic Blood Pressure Score Change | -5.0 mmHg | Standard Error 3.9 |
| Sham Treatment | Systolic Blood Pressure Score Change | -2.9 mmHg | Standard Error 4.2 |