Spinal Cord Stimulation for the Treatment of Major Depressive Disorder

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.

• Active transcutaneous spinal direct current stimulation (Device): Active anode electrodes placed at Thoracic 10 level, Cathode electrode placed on right shoulder.
• Sham transcutaneous spinal direct current stimulation (Device): Sham anode electrodes placed at Thoracic 10 level, Cathode electrode placed on right shoulder.

Primary outcomes

• 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 outcomes

• Number of Participants With Skin Redness [8 weeks]: Number of participants with skin redness in the active and sham tsDCS groups.
• 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.
• 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.
• 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.

Sex: All, ages: 18 Years to 55 Years

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.

Participant flow

Outcome results

• Montgomery Asberg Depression Rating Scale (MADRS) Score Change (Primary), Least squares mean, summed total scores: Active Treatment -21.7 +/- 2.3; Sham Treatment -14.6 +/- 2.5 (p =0.040)
• Number of Participants With Skin Redness (Secondary), Count of participants, Participants: Active Treatment 9; Sham Treatment 4
• Clinical Global Impression-Improvement (CGI-I) (Secondary), Least squares mean, total score of the scale: Active Treatment 1.3 +/- 0.3; Sham Treatment 2.0 +/- 0.3
• Montgomery Asberg Depression Rating Scale (MADRS) Sub-component Score (Item 2) Change (Secondary), Least squares mean, score on a scale: Active Treatment -3.2 +/- 0.4; Sham Treatment -1.8 +/- 0.4
• Patient Health Questionnaire-9 (PHQ-9) Score Change (Secondary), Least squares mean, score on a scale: Active Treatment -12.6 +/- 2.2; Sham Treatment -10.3 +/- 2.4
• Multidimensional Assessment of Interoceptive Awareness (MAIA) Score Change-Noticing Subscale (Secondary), Least squares mean, score on a scale: Active Treatment -0.0 +/- 0.5; Sham Treatment -0.2 +/- 0.5
• Binge Eating Scale (BES) Score Change (Secondary), Least squares mean, score on a scale: Active Treatment -7.3 +/- 2.7; Sham Treatment -3.0 +/- 3.0
• Four-Dimensional Symptom Questionnaire (4-DSQ)- Somatization Dimension Score Change (Secondary), Least squares mean, score on a scale: Active Treatment -3.3 +/- 2.1; Sham Treatment -6.9 +/- 2.3
• Systolic Blood Pressure Score Change (Secondary), Least squares mean, mmHg: Active Treatment -5.0 +/- 3.9; Sham Treatment -2.9 +/- 4.2
• Heart Rate Score Change (Secondary), Least squares mean, Beats per minute: Active Treatment 4.7 +/- 3.9; Sham Treatment 5.3 +/- 4.2
• Body Mass Index Change (Secondary), Least squares mean, kg/m^2: Active Treatment -0.3 +/- 2.0; Sham Treatment 1.5 +/- 2.2
• Adiponectin Level Change (Secondary), Least squares mean, ug/mL: Active Treatment -805 +/- 1640; Sham Treatment 1472 +/- 2409
• Leptin Level Change (Secondary), Least squares mean, ng/mL: Active Treatment -1.5 +/- 4.4; Sham Treatment 2.7 +/- 6.4
• Cortisol Level Change (Secondary), Least squares mean, nmol/L: Active Treatment -0.7 +/- 2.2; Sham Treatment -0.9 +/- 3.1
• Insulin Level Change (Secondary), Least squares mean, Milli-international Units/ Liter (mIU/L): Active Treatment -4.2 +/- 4.6; Sham Treatment -7.2 +/- 6.8
• Fibroblast Growth Factor-21 (FGF-21) Level Change (Secondary), Least squares mean, ng/ml: Active Treatment -13.3 +/- 53.2; Sham Treatment -30.9 +/- 78.1
• Fatty Acid (LCn-3) Level Change (Secondary), Least squares mean, Percentage change: Active Treatment -0.02 +/- 0.19; Sham Treatment -0.01 +/- 0.22

Adverse events

Time frame: During the eight week study duration.

Other adverse events by term

Limitations and caveats: This is a proof of concept pilot feasibility clinical trial with a small sample size.

• Results publication: Romo-Nava F, Awosika OO, Basu I, Blom TJ, Welge J, Datta A, Guillen A, Guerdjikova AI, Fleck DE, Georgiev G, Mori N, Patino LR, DelBello MP, McNamara RK, Buijs RM, Frye MA, McElroy SL. Effect of non-invasive spinal cord stimulation in unmedicated adults with major depressive disorder: a pilot randomized controlled trial and induced current flow pattern. Mol Psychiatry. 2024 Mar;29(3):580-589. doi: 10.1038/s41380-023-02349-9. Epub 2023 Dec 20. PMID 38123726

• Study Protocol and Statistical Analysis Plan (PDF, 2023-09-26)

• Francisco Romo-Nava, MD,PhD, Principal investigator, University of Cincinnati/ Lindner Center of HOPE