Closed-Loop Transcranial Alternating Current Stimulation for the Treatment of Major Depressive Disorder

Closed-Loop Transcranial Alternating Current Stimulation for the Treatment of Major Depressive Disorder: Double-Blind, Controlled Randomized Multicenter Clinical Trial

The purpose of this research study is to investigate a closed-loop transcranial alternating current stimulation (tACS) device to evaluate its ability to reduce symptoms of major depressive disorder

This study examines the efficacy of closed-loop transcranial alternating current stimulation (CL-tACS) for the treatment of major depressive disorder (MDD) in a double-blind, controlled parallel group multi-site clinical trial. 214 participants will be randomized into receiving 5 consecutive days of active or control CL-tACS (1:1 allocation) to achieve approximately 192 participants completing the primary endpoint at week 3, assuming a 10% lost to follow-up rate. Clinical assessments of depression and anxiety symptoms are performed at Screening, Baseline, Day 5, Follow-Up 1 (week 3), and Follow-Up 2 (week 5). Additional assessments of quality of life are included.

For subjects who are not considered responders at the Week 3 primary endpoint, there will be a phase 2 retreatment with active CL-tACS which will mirror the same 5-day protocol. Patients in this arm will complete additional data collection at Phase 2 baseline, Phase 2 Day 5, Phase 2 Follow-up 1 (phase 2 week 3), and phase 2 follow-up 2 (phase 2 week 5).

Inclusion Criteria:

1. ≥ 22 years of age;

2. with at least moderate symptom severity (HAM-D17 ≥ 17);

3. who are currently in a depressive episode;

4. who have used at least 1 antidepressant in the current or previous episode, but have not found adequate symptom relief or who were not able to tolerate medication side effects;

5. who, for 6 weeks prior to enrollment, are either;

   • not taking antidepressant medication, or:
   • are taking a stable psychiatric medication regimen with one or more stable antidepressant medication dose(s) and agree to continue the same regimen throughout study participation

6. if currently engaged in depression-focused psychotherapy, have maintained stable frequency of therapy for at least 8 weeks prior to enrollment and agree to continue the same regimen throughout study participation;

7. are able and willing to comply with the protocol and follow up schedule and protocol, in the opinion of the investigator;

8. who understand English and are able to provide written informed consent;

9. who are currently under the care of a psychiatric clinician or a primary care physician for major depressive disorder, and who agree to promptly inform the study staff of any change of psychiatric or mental health providers during study participation;

10. who agree to allow any and all forms of communication between the investigators/study staff and their current or past (within 2 years) healthcare providers;

11. who agree to provide the names and verifiable contact information (email and mailing addresses, mobile and/or land-line phone numbers, as applicable) for at least two persons (≥ age 18) who reside within a 60-minute drive of their residence and whom the research staff are at liberty to contact, as they deem necessary, to ensure participant safety for the duration of study participation;

Exclusion Criteria:

1. Subjects with current / past six months use of an external stimulation device for MDD, including electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), or other brain or cranial nerve stimulation;
2. Subjects with (lifetime) history of failure to response to an adequate trial of ECT, TMS, or implanted vagus nerve stimulation;
3. Subjects who currently receive esketamine, ketamine, or psilocybin treatment
4. Subjects who are pregnant or of childbearing potential and not using adequate contraception, as determined by the investigator;
5. Subjects who are breastfeeding.
6. Subjects whose current depressive episode had onset within 6 months post-partum;
7. Presence of active skin disorder on the forehead that could be exacerbated by stimulation electrodes in the opinion of the investigator.
8. Subjects with clinical or historical features which, in the opinion of the investigator, make them an inappropriate candidate for participation in this trial;
9. Subjects whose current depressive episode has not responded to 3 or more adequate trials of FDA approved antidepressant medications;
10. Subjects with current suicidal ideation with plan or intent, or suicidal behavior or preparation in the past 3 months, as determined by CSSRS assessment or by the Investigator;
11. Subjects with a diagnosis of epilepsy or unexplained seizures;
12. Subjects with a diagnosis or clinical history suggestive of bipolar disorder, hypomania, mania, or psychosis, as determined by the Investigator and/or by the DIAMOND assessment.
13. Subjects currently participating, or intending to participate (during the next 3 months) in another study involving an investigational drug or device treatment that, in the opinion of the investigator, could impact symptoms of MDD or use of the investigational device;
14. Subjects with a history of intracranial surgery;
15. Subjects with implanted neurostimulators, nonremovable or implanted electrical devices or intracranial metal objects, with the exception of dental metal;
16. Subjects with cognitive impairment or memory disorders, which, in the opinion of the investigator, could impact their ability to comply with study requirements;
17. Subjects currently meeting diagnostic criteria for obsessive compulsive disorder determined by the Investigator and/or by the DIAMOND assessment;
18. Subjects who meet DSM-V criteria for moderate/severe alcohol use disorder or other substance use disorders (except tobacco/nicotine) within the past 6 months as confirmed by the DIAMOND interview;
19. Subjects who meet DSM-V criteria for moderate/severe cannabis use disorder (CUD) within the past 6 months as confirmed by the DIAMOND interview. Subjects with recreational or prescription use (including medical marijuana cards) not considered moderate to severe CUD will be included.
20. Subjects with a current neurological condition or disease which, in the opinion of the investigator, is likely to manifest a depressive syndrome or symptoms that would substantially confound the diagnosis or serial assessment of major depressive disorder.