Transcranial Electric Stimulation Therapy (TEST) for Treatment Resistant Depression (TRD)

Background: People with TRD are often helped by electroconvulsive therapy (ECT). But ECT can affect memory and thinking. Researchers want to study a treatment called TEST that uses less electricity. Objective: To study the safety and feasibility of TEST and assess its antidepressant effects. Eligibility: Adults aged 25-64 with major depression that has not been relieved by current treatments. Design: Participants will be admitted to the NIH Clinical Center for 5 18 weeks over 2 3 treatment phases. Their medications may be adjusted. Participants will be interviewed about their depression, side effects, and other treatments they are receiving. They will complete questionnaires. They will give blood and urine samples. Their brain waves and heart rhythm will be recorded. They will take tests of memory, attention, mental functioning, and thinking. Participants will have magnetic resonance imaging (MRI) scans of the head and brain. They will lie on a table that slides in and out of the scanner. Pictures of brain chemicals will also be taken. They may complete tasks during the MRI. Participants will receive TEST and/or sham treatments. They may receive optional ECT. An intravenous catheter will be placed in an arm vein to receive general anesthesia. Two electrodes will be placed on the front of their head. An electric current will be passed from the ECT machine through the electrodes. For sham treatments, they will not receive the electric current. Their breathing, heart rate, brain function, blood pressure, and body movements will be measured. Participants will have 7 follow-up visits over 6 months. Visits can be done via telehealth. Participation will last for up to 42 weeks.

* 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 \=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.