DBS of the Habenula for Treatment- Resistant Major Depression

Study Overview
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Brief Summary
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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.

Official Title
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Deep Brain Stimulation of the Bilateral Habenula for Treatment- Resistant Major Depression: An Open Label Pilot Trial

Conditions
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Treatment Resistant Major Depression Disorder

Intervention / Treatment
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* Procedure: Deep brain stimuation system implantation


Participation Criteria
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Eligibility Criteria
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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;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: All subjects will receive bilateral surgical implantation of DBS system.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deep Brain Stimulation of Bilateral Habenula<br> | Procedure: Deep brain stimuation system implantation<br>* All subjects will receive bilateral surgical implantation of DBS system.The Medtronic DBS 3389 electrode is utilized in this study. The DBS system includes a dual-channel neurostimulator kit, lead kit, extension kit, clinician-operated wireless programmer, test stimulator, and patient controller.<br>* Other names: Activa RC System;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in the Hamilton Depression Scale(HAMD-17) score from baseline to 9 months | The score of the scale ranges from 0 to 50. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| changes in the Montgomery-Asberg Depression Rating Scale from baseline to 9 months | The score of the scale ranges from 0 to 60. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in the brain activity |  | Baseline (preoperative),one month, 9 months | 
| Side Effects |  | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Young Mania Rating Scale (YMRS) | YMRS is an eleven-item multiple choice diagnostic questionnaire which psychiatrists use to measure the severity of manic episodes. The score of the scale ranges from 0 to 60. Higher score means more severity of mania. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Changes in Hamilton Anxiety Scales(HAMA) | Clinician administered assessment.The score of the scale ranges from 0 to 56. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Global Assessment of Functioning Scale(GAF) | Clinician administered assessment.The score of the scale Scores range from 100 (extremely high functioning) to 1 (severely impaired). | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Columbia Suicide Severity Rating Scale (C-SSRS) | Clinician administered assessment.The Screener contains 6 yes or no questions in which respondents are asked to indicate whether they have experienced several thoughts or feelings relating to suicide over the past month and behaviors over their lifetime and past 3 months. Each question addresses a different component of the respondent's suicide ideation severity and behavior. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Changes in Beck Depression Inventory | Self-rating scale. The score of the scale ranges from 0 to 63. Higher score means more severity of depression. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Chang in Pittsburgh Sleep Quality Index | The Pittsburgh Sleep Quality Index (PSQI) is a self-report questionnaire that assesses sleep quality over a 1-month time interval. The measure consists of 19 individual items, creating 7 components that produce one global score ranging from 0 to 21. The high score means poor quality of sleep. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| World Health Organization Quality of Life-BREF(WHO-BREF) | The World Health Organization Quality of Life - BREF (WHOQOL-BREF) is a self-report questionnaire which assesses 4 domains of quality of life (QOL): physical health, psychological health, social relationships, and environment. It contains 26 items which is a 5 points scale. The higher score means better quality of life. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| the MOS item short from health survey (SF-36) | SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting and are now widely utilized by managed care organizations and by Medicare for routine monitoring and assessment of care outcomes in adult patients. The higher score means better quality of life. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form | The scoring of the Q-LES-Q-SF involves summing only the first 14 items to yield a raw total score. The last two items are not included in the total score but are stand-alone items. The raw total score ranges from 14 to 70. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Sheehan Disability Scale | Self-rating scale. The SDS is a composite of three self-rated items designed to measure the extent to which three major domains in the patient's life are functionally impaired by psychiatric or medical symptoms. The SDS assesses functional impairment in three major life domains: work, social life/leisure activities, and family life/home responsibilities. The higher scores mean more severity of disability. | Baseline (preoperative),one month, 3 months, 6 months, 9 months | 
| Changes in Neuropsychological measures(Scores of CANTAB tasks) | Neuropsychological measures contains six tasks which are Stop Signal Task, Spatial Working Memory, Paired Associated Learning, Stocking of Cambridge, Intra Extra dimensional Set Shifting, Reaction time Task | Baseline (preoperative),3 months, 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Resistant Major Depressive Disorder, Bilateral Habenula