7 patients were included in this study which aimed for 13 participants. Preliminary data were sufficient for developing further study.

The habenula(Hb) is an epithalamic structure located at the center of the dorsal diencephalic conduction system, a pathway involved in linking forebrain to midbrain regions. An increasing number of studies indicates that overactivity in the lateral habeluna(LHb) is present during depressed states, where it could drive the changes in midbrain activity linked to depression. Deep brain stimulation(DBS) of the major afferent bundle (i.e., stria medullaris thalami) of the LHb can treat treatment-resistant major depression(TRD). There is no clinical case of directly stimulating habeluna for treatment TRD. This research will investigate effectiveness and safety of bilateral DBS to habenula for patients with TRD. This study will also use structural and functional MRI to explore the underlying mechanism of Hb's effects on TRD.

Inclusion Criteria:

• Men and women(non-pregnant) aged 18-65 years old;
• DSM-5 diagnosis (assessed by Structured Clinical Interview for DSM-5) of a current major depressive episode(MDE), either nonpsychotic unipolar major depressive disorder (MDD) or bipolar disorder (BD);
• Chronic illness with current MDE ≥ 24 months duration and/or recurrent illness with at least a total of 4 lifetime episodes (including current episode ≥ 12 months) and a minimum of 5 y since the onset of the first depressive episode;
• For subjects with a bipolar disorder: the last manic or hypomanic episode must have been ≥ 24 months before study enrollment and patients must be maintained on a mood stabilizer (e.g. lithium or another mood stabilizer approved for bipolar disorder)
• Treatment resistance defined as Failure of at least 3 adequate treatments from at least two distinctly different classes (SSRI, SNRI, NaSSA, TCA+, lithium-addition) for a period of 6-8 weeks. If diagnosed as bipolar, failure to respond to (or inability to tolerate) a minimum of three treatments approved for bipolar disorder, including lithium and at least one medication FDA-approved for bipolar depression (e.g., olanzapine/fluoxetine combination, quetiapine, lurasidone).
• At least 1 session of ECT, for which the series of ECT was terminated either due to adverse effects or insufficient response (including at least 6 sessions of bilateral ECT). Or unable to recieve ECT.
• Symptom Severity: HAMD-17 total ≥21;
• Stable antidepressant medical regimen for the month preceding surgery;
• Anticipates a stable psychotropic medication regimen in the next 12 months;
• Able and willing to give written informed consent;
• Modified mini-mental state examination (MMSE) score ≥ 27；

Exclusion Criteria:

• Schizophrenia /history of psychosis unrelated to MDD;
• Severe personality disorder (assessed by SCID-II);
• Alcohol or substance abuse/dependence within 6 months, excluding nicotine dependence;
• Current substantial suicidal risk as defined by a plan or clear immediate intent for self-harm, or had a serious suicide attempt within the last year;
• Neurological disease (e.g., Parkinson's disease)
• Any history of seizure disorder or hemorrhagic stroke;
• Abnormal brain MRI ;
• Previous sterosurgery;
• Any medical contraindication to surgery;
• Does not have adequate family/friend support as determined by psychological screening and/or interview;
• Unable to maintain a stable psychotropic medication regimen in the next 12 months;
• Pregnant or has plans to become pregnant in the next 12 months;