* INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
1. Provision of a signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female, ages 25 through 64 years.
4. Meeting structured clinical interview for the DSM 5 (SCID) criteria for major depressive disorder, bipolar I disorder, or bipolar II disorder.
5. Currently have TRD as defined by a major depressive episode with lack of remission of depressive symptoms following two trials of different medication or one medication trial and one rTMS trial approved for unipolar or bipolar depression at adequate dosage and duration treatment consistent with an Antidepressant Treatment History Form (ATHF) confidence level \>=3.
6. Score \>= 25 on the Montgomery-Asberg Depression Rating Scale (MADRS) and a score \>=2 on item 1 at screening or for individuals with bipolar depression, score \>= 25 on the Bipolar Depression Rating Scale (BDRS) at screening.
7. Score \<=12 on the Young Mania Rating Scale (YMRS) and a score \<= 1 on item 1 at screening.
8. Willingness to: (a) provide written permission, as requested, to allow any and all forms of communication between the Investigator/Research Staff and any healthcare provider who currently provides and/or has provided service to the patient/subject within two years of study enrollment; and (b) provide the name and verifiable contact information of a person whom they trust to be an emergency contact whom research staff is at liberty to contact for the duration of study participation and who could serve as a legally authorized representative (LAR) if needed.
9. Agreement to remain on the same daily dose of all psychiatric medication(s) without taking any new psychiatric medication(s) for a minimum of 6 weeks (42 days) prior to the baseline assessment and through the completion of Study Phase III (Study Phase IV is the 6-month Follow-up Phase) unless advised otherwise by the Investigator
10. Agreement that dosage reduction of any medication taken for a psychiatric condition must be completed at least 4 weeks (28 days) prior to the baseline assessment and must remain unchanged thereafter through the completion of Study Phase III (Study Phase IV is the 6- month Follow-up Phase), unless advised otherwise by the Investigator
11. Agreement to remain on the same daily dose of psychiatric medication from the start of the baseline assessment / Phase I through the completion of the final treatment Study Phase III (Study Phase IV is the 6-month Follow-up Phase), unless advised otherwise by the Investigator.
12. For females of reproductive potential: use of contraception, which in the opinion of the Investigator is highly effective, for at least 1 month prior to screening and agreement to use such a method during study participation, except during the 6-month follow up.
13. Ability of the participant to understand and be willing to sign a written informed consent document as determined by the Investigator.
ECLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
1. Pregnancy or nursing or women planning to become pregnant during study period, except for the 6-month follow up phase.
2. A history of addiction to, dependence on, abuse of, or misuse of alcohol or any controlled, illicit, or illegal substance (excluding nicotine) within the past one year
3. Expression of recent or current active suicidal ideas and an explicit plan or intent, in the opinion of the Investigator or answering YES to questions 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) or scoring \>4 on Montgomery-Asberg Depression Rating Scale (MADRS) item 10.
4. Presence of any disease, medical condition or physical condition that, in the opinion of the Investigator, may compromise, interfere with, limit, effect or reduce the:
1. subject s ability to participate in any of the items listed in the Schedule of Activities
2. integrity of the data or
3. subject s ability to complete the full duration of the study.
5. Mood disorder is, in the opinion of the Investigator, significantly influenced or caused by an underlying medical or neurological condition, for example, multiple sclerosis or fibromyalgia
6. History of serious, potentially life-threatening reaction to methohexital or succinylcholine.
7. Clinically significant psychiatric comorbidity as determined by clinical interview and in the opinion of the Investigator
8. Past or present medical or neurological condition, disease, disorder or injury that, in the opinion of the Investigator, may significantly increase the potential risks of study participation, reduce or compromise a subject s ability to fully comply with all study requirements for the duration of the study or may compromise the integrity of the data. Past or present medical or neurological condition, disease, disorder or injury that, in the opinion of the Investigator, may significantly increase the potential risks of study participation, reduce or compromise a subject s ability to fully comply with all study requirements for the duration of the study or may compromise the integrity of the data.
9. History of seizure except those therapeutically induced by ECT, except for childhood febrile seizures.
10. History of any of the following:
1. intracranial surgery
2. cranial metal implants
3. presence of devices that may be affected by MRI (pacemaker, medication pump, cochlear implant, implanted brain stimulator, vagus nerve stimulator
4. history of head trauma associated with a brain imaging study that shows probable or definite evidence of a post-traumatic abnormality as determined by a neuroradiologist and which the Investigator deems clinically significant at screening.
11. Any of the following treatment histories:
Failure to respond to adequate ECT treatment consistent with an ATHF confidence level \>=3 in current or any previous episode
Lifetime history of treatment with deep brain stimulation
Use of any investigational drug or device within 4 weeks of the screening
12. Inability to pass the Evaluation to Sign A Consent Form test for adequate comprehension of the study for any reason including limitations related to use of the English language.
13. Positive HIV test.
14. Being an NIMH employee or an immediate family member of an NIMH employee.
15. Presence of any condition that, in the judgment of the investigator, may hinder completion of the procedures required by the study protocol.
