The MOOD Study - External Combined Occipital and Trigeminal Nerve Stimulation (eCOT-NS) for the Treatment of Major Depressive Disorder (MDD)

Inclusion Criteria:

1. Males and females 18-70 years of age:

2. Up to 124 randomized subjects aged 22-70

3. Up to 36 randomized subjects aged 18-21

4. Primary diagnosis of unipolar major depressive disorder by DSM-V criteria.

5. Current MDD episode lasts up to three years.

6. Score on the Hamilton Depression Rating Scale (HDRS21) ≥ 20

7. Symptoms of current major depressive episode that, as determined by theInvestigator, for the current episode and according to the Antidepressant TreatmentResistance Form (ATRF) or Antidepressant Treatment Intolerance Form (ATIF):

• Did not respond or have insufficiently responded by less than 50% improvement;dose and duration defined & rated at minimum confidence level 3 on the ATRF;

• Did not respond or has insufficiently responded to at least one but no morethan four adequate trials of antidepressant medications (4 ≥ ATRF ≥1) or

• Did not respond or has insufficiently responded due to poor tolerability to atleast two inadequate antidepressant medication trials (ATIF ≥2).

6. Subject must be on at least one (1) antidepressant medication (minimum therapeuticdose not required if tolerability precluded further dose titration) and is willingto remain on the same daily dose of antidepressant medication(s) for a minimum of 28days prior to randomization and thereafter for the duration of the study.

7. For subjects receiving current depression focused psychotherapy: psychotherapyinitiated at least 1 month prior to baseline visit with a stable frequency of visitsregimen, in the opinion of the Investigator.

8. Subject is able to provide written Informed Consent and is capable of complying withthe specified study requirements, as determined by the Investigator.

9. Subject has cognitive and/or motor skills needed to operate a smartphone and can becontacted by phone, as determined by the Investigator.

Exclusion Criteria:

1. History of intracranial surgery.

2. Current denervation in one or more of the following: the supraorbital orsupratrochlear branches of the trigeminal nerve, or the greater occipital branch ofthe occipital nerve.

3. An implanted neurostimulators or any implanted metallic or electronic device in thehead, a cardiac pacemaker or an implanted or wearable defibrillator, except fordental implants.

4. Skin lesion, scars, or inflammation at the region of the stimulating electrodes.

5. Subjects with a history of traumatic brain injury (TBI), defined as a disruption inthe normal function of the brain that can be caused by a bump, blow, or jolt to thehead, or penetrating head injury, within 3 months of study enrollment.

6. Pregnancy or Lactation.

7. Women of reproductive age not using a reliable contraceptive method as determined bythe Investigator.

8. In the opinion of the Investigator, subjects with a psychiatric history consistentwith, suspicious for, or diagnostic of, bipolar depression or depression associatedwith psychosis.

9. Borderline personality disorder, defined by DSM-V criteria, that in the judgement ofthe Investigator is likely to complicate the assessment of clinical response tostudy treatments or limits the patient's ability to comply with study procedures

10. Subjects who, within one (1) year of study enrollment, have a history consistentwith, suspicious for or diagnostic of, any of the following: psychosis, psychoticdisorder, schizophrenia or schizoaffective disorder, in the opinion of theInvestigator.

11. Subjects who demonstrate or have a history of any cognitive disorder or impairment,memory loss, dementia, confusion or delirium that, in the opinion of theInvestigator, may compromise the integrity of the study data or impact the abilityof the subject to comply with the study requirements.

12. Past 12 months active suicidal intent or plan as defined by a "yes" answer to Q4 orQ5 on the Columbia-Suicide Severity Rating Scale, (C-SSRS) or with a history ofsuicide attempt in the past twelve months.

13. Subjects currently (past month) meeting diagnostic criteria for Obsessive-CompulsiveDisorder or post-traumatic stress disorder and that is their primary diagnosis.

14. Subjects meeting the DSM-V criteria for alcohol use disorder or other substance usedisorder (not including tobacco/nicotine) within six (6) months prior to studyenrollment.

15. The subject has any past or present medical condition, disease, illness, disorder orinjury that, in the opinion of the Investigator, may reduce or hinder the subject'sability to fully comply with all study requirements for the duration of the study ormay confound the integrity of the study data.

16. Participation in a previous study with the Relivion®DP or the Relivion® device.

17. Treatment with Transcranial Magnetic Stimulation (TMS) in the past 6 months.

18. Current treatment with any other approved or investigational brain stimulationtherapies (i.e. Vagus or trigeminal nerve Stimulation, tDCS, TES).

19. Failure to receive clinical benefit from an adequate trial of ECT in the current ora past depressive episode in the opinion of the Investigator.

20. Subject having received Botox treatment in the head or neck region within 90 daysprior to study enrollment.

21. Subject having received supraorbital or occipital nerve blocks within 1 month priorto enrollment.

22. Head circumference smaller than 51 centimeters or larger than 60 centimeters.

23. Current neurological condition or disease which, in the opinion of the investigator,is likely to manifest a depressive syndrome or symptoms that would substantiallyconfound the diagnosis or serial assessment of major depressive disorder.

24. Subjects participating in other clinical trials evaluating experimental treatmentsor procedures.