Individualized Non-invasive Brain Stimulation for the Treatment of Major Depressive Disorder (CL-tACS RCT)

Closed-Loop Transcranial Alternating Current Stimulation (CL-tACS) for the Treatment of Major Depressive Disorder: Double-Blind, Sham-Controlled Randomized Pilot Study

The purpose of this research study is to study a closed-loop transcranial alternating current stimulation (tACS) device to evaluate feasibility of the product in a clinical trial and collect preliminary data on potential effects on symptoms of depression in people with major depressive disorder.

Study Overview

• Status: Active, not recruiting
• Conditions: Transcranial Alternating Current Stimulation; Depression - Major Depressive Disorder
• Intervention / Treatment: Device: Closed-loop tACS; Device: Sham Comparator

Detailed Description

The purpose of this study is to investigate device feasibility and performance of the XCSITE 100 Pro V2 device and assess preliminary efficacy of closed-loop transcranial alternating current stimulation (CL-tACS) for reducing symptoms of major depressive disorder (MDD) in a double-blind, sham-controlled, parallel group, single-site clinical trial. A total of 40 participants will be randomized to receive active or sham CL-tACS via carbon-silicone electrodes for up to 40 minutes over 5 consecutive days. Device feasibility and performance data will be collected from every stimulation session. Clinical assessments of depression and related symptoms will be performed at Baseline (Day 1), End Of Treatment (EOT; Day 5), and Follow-Up (FUP, 2-weeks post-treatment, Day 19). High-density electroencephalography (HD-EEG) will be performed at Baseline, EOT and FUP. An optional MRI will be performed up to 30 days before, or on Baseline, to provide anatomical data for EEG brain connectivity analysis.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27516
      • Carolina Center for Neurostimulation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Any gender, aged 18 - 70
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• DSM-5 diagnosis of unipolar, non-psychotic MDD as evidenced by the DIAMOND
• HDRS-17 score ≥14
• Low suicide risk (defined for this study as no active suicidal ideation in the past month and no suicide attempts, preparatory actions, or significant non-suicidal self-harm in the previous 2 years). Risk will be assessed utilizing the C-SSRS screen and triage version with further exploration of positive responses.
• Capacity to understand all relevant risks and potential benefits of the study (informed consent)
• For people of childbearing potential: use of highly effective contraception as determined by the Investigator for at least 1 month prior to screening and agreement to use such a method during study participation

Exclusion Criteria:

• DSM-5 diagnosis of severe alcohol use disorder (AUD) within the last 12 months, as evidenced by the DIAMOND
• DSM-5 diagnosis of moderate to severe substance use disorder (excluding tobacco) within the last 12 months, as evidenced by the DIAMOND
• Lifetime history of bipolar disorder, as evidenced by DIAMOND
• Schizophrenia spectrum and other psychotic disorders, as evidenced by DIAMOND
• History of autism spectrum disorder
• Initiated any new psychotropic medication in the 6 weeks prior to screening or had a dose change in the preceding 6 weeks
• Initiated a new course of psychotherapy in the 6 weeks preceding screening
• Received any neurostimulation treatment in the 6 weeks preceding screening
• History of seizures (excluding febrile seizures in childhood or Electroconvulsive Therapy (ECT) induced seizures)
• Neurological disorders that would increase risk of participation or present a significant confounder in the opinion of the investigator (for example, dementia, history of stroke, Parkinson's disease, multiple sclerosis, history of traumatic brain injury with prolonged loss of consciousness, ruptured cerebral aneurysm, previous CNS radiation)
• Previously failed to respond to ECT or transcranial magnetic stimulation (TMS)
• Prior brain surgery and/or brain implants
• Implanted medical device that uses electricity
• Current pregnancy or lactation
• Currently enrolled in another clinical trial for depression
• For the optional MRI session only: Contraindication to MRI according to MRI Screening Form
• Unstable medical disorder or anything that would place the participant at increased risk or preclude the participant's full compliance with or completion of the study, in the opinion of the Investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Device Feasibility
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Closed-loop tACS; Closed-loop individual alpha tACS daily for five consecutive days.	Device: Closed-loop tACS; Individual alpha tACS; Other Names: CL-tACS
Sham Comparator: Sham Closed-loop tACS; Sham closed-loop individual alpha tACS daily for five consecutive days.	Device: Sham Comparator; Sham stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correct Assignment by Device of Study Arm	Successful assignment by device software to correct study arm for each participant for each session, Day 1 (D1) through Day 5 (D5). Measured as percentage of successful assignments compared to intended programming.	5 days
Accuracy of Device Study Arm Parameters by Device	Verification of correct study arm parameters applied by device for each participant for each session, Day 1 (D1) through Day 5 (D5).	5 days
Accuracy of Stimulation Initiation Based on EEG by Device	Verification of correct stimulation initiation decisions for each evaluated EEG window by device for each participant for each session, Day 1 (D1) through Day 5 (D5).	5 days
Accuracy of Device Logs Uploaded to Cloud by Device	Verification of equivalence between logs stored on local device and corresponding logs uploaded to cloud for each participant for each session, Day 1 (D1) through Day 5 (D5).	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HDRS-17 Change	Change in HDRS-17 from two week follow-up (FUP) to D1 between Experimental and Sham Comparator study arms; minimum value is 0, maximum value is 52. Higher scores indicate worse outcome.	21 Days
Change in Alpha Oscillation Power	Change in EEG alpha oscillation power between D1 and D5 between Experimental and Sham Comparator study arms.	5 Days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Alpha Oscillation Power and Connectivity	Change in HD-EEG alpha oscillation power and connectivity at D1, D5, and FUP between Experimental and Sham Comparator study arms.	21 Days
Remission Rate	Difference in remission rates between Experimental and Sham Comparator study arms at FUP. Remission defined as HDRS-17 score of less than or equal to 7.	21 Days
Response Rate	Difference in response rates between Experimental and Sham Comparator study arms at FUP. Response defined as greater than or equal to 50% reduction in HDRS-17 score from D1 to FUP.	21 Days
SSRI Effect on HDRS-17 Change	Change in HDRS-17 for Experimental study arm from two week follow-up (FUP) to D1 between patients on SSRI medication and patients not on SSRI medication; minimum value is 0, maximum value is 52. Higher scores indicate worse outcome.	21 Days
Change in Quick Inventory of Depressive Symptomatology (QIDS)	Change in QIDS from D1 to FUP between Experimental and Sham Comparator study arms; minimum value is 0, maximum value is 27. Higher scores indicate worse outcome.	21 Days
Change in Snaith-Hamilton Pleasure Scale (SHAPS)	Change in SHAPS from D1 to FUP between Experimental and Sham Comparator study arms; minimum value is 0, maximum value is 14. Higher scores indicate worse outcome.	21 Days
Change in Quality of Life Enjoyment and Satisfaction Questionnaire, short form (Q-LES-Q-SF)	Change in Q-LES-Q-SF from D1 to FUP between Experimental and Sham Comparator study arms; minimum value is 0, maximum value is 14. Higher scores indicate worse outcome.	21 Days
Change in Clinical Global Impression Scale (CGI)	Change in CGI from D1 to FUP between Experimental and Sham Comparator study arms; CGI scale contains two scoring components, 1) Severity of Illness (0-7) and 2) Global Improvement (0-7). Higher scores in component 1 indicate worse symptoms while higher numbers in component 2 indicate worse clinical outcomes.	21 Days

Collaborators and Investigators

• Sponsor: Pulvinar Neuro, LLC
• Collaborators: National Institute of Mental Health (NIMH); University of North Carolina, Chapel Hill
• Investigators: Principal Investigator: David Rubinow, MD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Alexander ML, Alagapan S, Lugo CE, Mellin JM, Lustenberger C, Rubinow DR, Frohlich F. Double-blind, randomized pilot clinical trial targeting alpha oscillations with transcranial alternating current stimulation (tACS) for the treatment of major depressive disorder (MDD). Transl Psychiatry. 2019 Mar 5;9(1):106. doi: 10.1038/s41398-019-0439-0.
• Schwippel T, Pupillo F, Feldman Z, Walker C, Townsend L, Rubinow D, Frohlich F. Closed-Loop Transcranial Alternating Current Stimulation for the Treatment of Major Depressive Disorder: An Open-Label Pilot Study. Am J Psychiatry. 2024 Sep 1;181(9):842-845. doi: 10.1176/appi.ajp.20230838. Epub 2024 Aug 7. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2025
• Primary Completion (Estimated): May 22, 2026
• Study Completion (Estimated): June 22, 2026

Study Registration Dates

• First Submitted: January 28, 2025
• First Submitted That Met QC Criteria: March 11, 2025
• First Posted (Actual): March 13, 2025

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Depression; Major Depressive Disorder; tACS; Transcranial Alternating Current Stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major
• Other Study ID Numbers: 24-2166; R44MH119872 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No