The Efficacy and Prediction of Deep Brain Stimulation for Treatment-resistant Depression

Study Overview
=================
Brief Summary
-----------------
Several open-label trials have shown the therapeutic promise of deep brain stimulation (DBS) targeted to striatal and surrounding capsular areas in treatment-resistant depression (TRD). However, the results of placebo-controlled trials have been mixed, with one showing a large difference between active and sham DBS and another finding no difference. Main aim of this study is establishing whether active DBS results in more treatment responders than sham DBS. Secondary aims are establishing an adverse events profile, establishing effects on quality of life,neuropsychological and neuroimaging measures, and finding predictors of response.

Detailed Description
-----------------
Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder, with an estimated lifetime prevalence of 14.6% across high-income countries.Effective therapeutic options for MDD include psychotherapy, different classes of antidepressants, and electroconvulsive therapy (ECT). Nevertheless, up to 30% of patients do not respond to four consecutive antidepressant strategies and 52% of pharmacotherapy resistant patients do not respond to ECT.Such patients are designated an advanced stage of Treatment Resistant Depression (TRD), which is associated with more hospitalizations, more suicide attempts, and higher costs than non-TRD patients. Deep Brain Stimulation (DBS) is a promising therapeutic option for TRD patients. DBS consists of implanting electrodes in specific brain areas and then optimizing stimulation parameters (e.g. voltage, frequency, pulse width) to modulate brain activity of the targeted area. Since 2005, several open label trials have reported promising effects of DBS in TRD, targeting different brain structures involved in the neurobiology of MDD: the Subcallosal Cingulate Gyrus (SCG),Medial Forebrain Bundle (MFB),Ventral Capsule/Ventral Striatum (VC/VS), and Nucleus Accumbens (NAc). Response rates, defined as a symptom decrease of at least 50%, range from 30% to 90% with most studies finding a response rate around 50%. However, results of the first two randomized trials are mixed. The first randomized, controlled trial (RCT) of VC/VS DBS in TRD did not find differences in response rates following active (3 of 14 patients) or sham stimulation (2 of 15 patients) after four months of stimulation. In contrast, our group found a strong antidepressant effect in 16 patients with TRD following active ventral Anterior Limb of the Internal Capsule (vALIC) DBS compared to sham stimulation in a randomized crossover phase. Therefore, this trial aims to establishing whether active DBS results in more treatment responders than sham DBS. Secondary aims are establishing an adverse events profile, establishing effects on quality of life,neuropsychological and neuroimaging measures, and finding predictors of response.

Official Title
-----------------
The Efficacy and Prediction of Deep Brain Stimulation for Treatment-resistant Depression

Conditions
-----------------
Major Depressive Disorder, Deep Brain Stimulation

Intervention / Treatment
-----------------
* Device: Deep brain stimulation(Active)
* Device: Deep brain stimulation(sham)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Primary diagnosis: Major Depressive Disorder according to the ICD-10 criteria based on a psychiatric interview Age: 18-65 years old HAMD-17 total ≥17 Chronic illness with current episode ≥ 24 months duration and/or Illness with at least a total of 4 lifetime episodes (including current episode≥ 12 months) and a minimum of 5 years since the onset of the first depressive episode Treatment refractory 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 or more weeks. Adequate psychotherapy. 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); unavailable, rejective or intolerable to ECT remain stable with the current anti-depressive medicine for the last month Able and willing to give written informed consent Able to fully understand the consequences of the procedure Exclusion Criteria: Schizophrenia /history of psychosis unrelated to MDD Severe personality disorder (assessed by SCID-II) Abnormal brain MRI Neurological disease (e.g., Parkinson's disease) Previous sterosurgery Any medical contraindication to surgery

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study starts with a longitudinal, 6 months' open-label phase followed by a randomized, double blind crossover phase. In the crossover phase, patients are randomized to active DBS for 1 week, followed by sham DBS for 1 week, or vice versa.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active DBS then Sham DBS<br>After 6 months open-lable period, some patients will take DBS ON for one week with the optimal stimulation parameters and then take DBS OFF for one week. | Device: Deep brain stimulation(Active)<br>* Active DBS with the optiomal parameters<br>* Other names: DBS;Device: Deep brain stimulation(sham)<br>* Sham DBS with 0V Amplitude<br>* Other names: DBS;|
| Experimental: Sham DBS then Active DBS<br>After 6 months open-lable period, some patients will take DBS OFF for one week and then take DBS OFF for one week with the optimal stimulation parameters. | Device: Deep brain stimulation(Active)<br>* Active DBS with the optiomal parameters<br>* Other names: DBS;Device: Deep brain stimulation(sham)<br>* Sham DBS with 0V Amplitude<br>* Other names: DBS;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in the Hamilton Depression Scale(HAMD-17) score | Effect size of active compared to sham stimulation score before and after the sham and treatment periods. The score of HAMD-17 ranges from 0 to 50. Higher HAMD-17 score indicates more severe depression. | Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in the Montgomery-Asberg Depression Rating Scale(MADRS) | Effect size of active compared to sham stimulation score before and after the sham and treatment periods. The score of the scale ranges from 0 to 60. Higher MADRS score indicates more severe depression. | Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 
| changes in the Quick Inventory of Depression Scale(QIDS-SR16) | Effect size of active compared to sham stimulation score before and after the sham and treatment periods. The score of the scale ranges from 0 to 42. Higher QIDS-SR16 score indicates more severe depression. | Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 
| changes in the Depression and Somatic Symptoms Scale(DSSS) | Effect size of active compared to sham stimulation score before and after the sham and treatment periods. The score of the scale ranges from 0 to 66. Higher DSSS score indicates more severe depression and anxiety. | Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 
| changes in the Dimensional Anhedonia Rating Scale(DARS) | DARS is a self-reported dynamic scale that measures desire, motivation, effort and consummatory pleasure across hedonic domains. Higher scores indicate lower degrees of anhedonia. | Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 
| changes in Hamilton Anxiety Scales(HAMA) | Clinician administered assessment.The score of the scale ranges from 0 to 56. The higher scores means more severe anxiety. | Baseline (preoperative),one month, 3 months, 6 months, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 
| changes in 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, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 
| changes in 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, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 
| changes in 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, 6.25 months, 6.5 months, 9 months, 12 months, 18months | 
| changes in Neuropsychological measures(Scores of Thinc-it tasks) | Neuropsychological measures contains six domains of cognition which are episodic memory, working memory,attention, executive functions, psychomotor speed and social cognition. | Baseline (preoperative), 6.25 months, 6.5 months, 18months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Treatment Resistant Depression, Deep Brain Stimulation, Ventral Capsule/Ventral Striatum