Treatment resistant depression (TRD) is a major global health concern, and there is a crucial need to develop novel effective treatments.

The medial forebrain bundle (MFB) is a recently described DBS target, with reported rapid onset of antidepressant effects. A recent small randomized trial reported a 100% response rate. The subcallosal cingulate cortex (SCC) is the most commonly used target in DBS for depression.

Herein, the investigators will conduct a sham-controlled randomized trial of DBS to the MFB or SCC for TRD.

Eight patients with TRD will be treated with DBS to the MFB. At approximately 2 weeks postoperartively, stimulation will be initiated in all patients. Voltage and contact position will be altered initially, looking for optimal and stabilized responses in depressive symptoms, while trying to minimize any side effects.

Following this 6 month open-label optimization phase, patients will be then undergo randomization to receive 2 weeks of stimulation followed by 2 weeks of sham stimulation, or vice versa. These 2 week phases will be separated by a 1 week washout period. Depressive symptoms will be evaluated at the end of each 2 week phase, then patients will resume open-label stimiulation.

Inclusion Criteria:

1. Men and women ≥20 and ≤80 years of age.

2. Patients who are able and willing to give consent and physically and practically able to attend study visits, as determined by both study Psychiatrist and the surgeon.

3. DSM-V diagnosis of major depressive disorder or bipolar II,

4. At least 5-year illness history of the primary disorder and at least 6 months since the onset of the first episode of major depression.

5. A minimum score of 20 on the Hamilton Depression Rating Scale (HAMD) when depressed)

6. Medication-refractoriness as determined by an adequate dose and duration of standard psychiatric treatments (including psychotherapy and/or pharmacology) as determined by two psychiatrists associated with the study. Including specifically:

   1. Failed to respond or tolerate adequate trial of three or more medications accepted as first line in the treatment of depression
   2. Failed to respond or tolerate augmentation with or combination of at least 2 medications known to be first line treatments for depression
   3. An adequate trial of cognitive behavioural therapy or other evidence-supported psychotherapy, delivered by a therapist experienced in treating depression

7. A consistent dose of any and all medications in the 30 days prior to study entry.

8. Women of childbearing potential must agree to use a contraception method throughout the study.

Exclusion Criteria:

1. Past or current evidence of psychosis or mania
2. Active neurologic disease, such as epilepsy
3. Alcohol or substance dependence or abuse in the last 6 months, excluding caffeine and nicotine
4. Current active suicidal ideation
5. Any contraindication to MRI scanning
6. Presence of significant cognitive impairment
7. Likely to relocate or move out of the country during the study's duration
8. Presence of clinical and/or neurological conditions that may significantly increase the risk of the surgical procedure.
9. Currently pregnant (as determined by history and serum HCG) or lactating; for females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation

An independent researcher will perform the randomization and institute the sham/active stimulation, allowing for continued blinding of participants/care providers/investigators/outcomes assessors.