Treatment-resistant Depression
Conditions
Keywords
Deep Brain Stimulation, Treatment-resistant depression, Medial forebrain bundle
Brief summary
The primary objective of this multicenter, randomized, sham-controlled, double blind (patient and observer blinded) clinical trial is to assess the antidepressant effect of Deep Brain Stimulation (DBS) in patients with treatment resistant major depression using the Boston Scientific implantable Vercise™ GEVIA™ DBS system compared to sham.
Detailed description
The main objective of this clinical trial is to assess the putative antidepressant efficacy of a therapeutic method called Deep Brain Stimulation (DBS) in patients suffering from severe, treatment-resistant depression, i.e. in patients who have not sufficiently improved under established antidepressant therapies (such as psychotherapy, antidepressant drug therapy, and electroconvulsive therapy). DBS, also known as "brain pacemaker" therapy, is a neurosurgical therapeutic method that is widely established for the treatment of other conditions such as Parkinson's disease. However, DBS is not yet approved for the treatment of patients with depression. In order to initiate DBS treatment, a neurosurgical procedure is performed in which electrodes are placed in a brain region termed 'medial forebrain bundle' (MFB). The electrodes are then used to stimulate this region with electric pulses. From previous investigations and studies with small numbers of patients, it is believed that DBS might have a positive effect on depressive symptoms in patients treated with the method.
Interventions
DEVICEVercise GEVIA deep brain stimulation (DBS) system
DBS to the superolateral branch of the Medial Forebrain Bundle (slMFB)
Sponsors
University Hospital Freiburg
Boston Scientific Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
multicenter, randomized, sham-controlled, double blind (patient and observer blinded)
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Major depression (MD), severe, unipolar, or bipolar in an acute depression episode. 2. German mother tongue or fluent. 3. Male or female patients ≥20 and ≤75 years. 4. Hamilton Depression Rating Scale (HDRS-28) score of \>21. 5. Global Assessment of Function (GAF) score of \<45. 6. At least 4 episodes of depression or one chronic episode \>2 years. 7. Failure to respond to 1. adequate trials of primary antidepressants from at least 3 different classes (\>5 weeks at the maximum recommended or tolerated dose) and 2. adequate trials of augmentation/combination of a primary antidepressant (\>3 weeks at the usually recommended or maximum tolerated dose) using at least 2 different augmenting/combination agents (lithium, T3, stimulants, neuroleptics, anticonvulsants, buspirone, or a second primary antidepressant) and 3. an adequate trial of electroconvulsive therapy (ECT) (\>6 treatments) and an adequate trial of individual psychotherapy (\>20 sessions with an experienced psychotherapist). 8. Able to give written informed consent. 9. Compliance to participate in the study. 10. Drug free or on stable drug regimen at least 6 weeks before study entry.
Exclusion criteria
1. Current or past non-affective psychotic disorder. 2. Any current clinically significant neurological disorder or medical illness affecting brain function, other than motor tics or Gilles de la Tourette syndrome. 3. Any clinically significant abnormality on preoperative magnetic resonance imaging (MRI), any contraindications to perform a planned MRI to visualize the slMFB. 4. Any surgical contraindications to undergoing DBS like deformed or displaced or not discernable target region, scarring after brain disease (infarction), need for continuous anticoagulation that cannot be bridged in order to obtain normal coagulation, present risks for anesthesia or any brain or scalp injury (even after intracranial surgery). 5. Current or unstably remitted substance abuse (aside from nicotine). 6. Pregnancy, women of childbearing age not using effective contraception and breast feeding women. 7. History of severe personality disorder. 8. Acute suicidal ideation. 9. Patients with advanced stage cardiovascular disease. 10. Patients under immunosuppressive or chemo therapy because of malignant disease. 11. Patients who had previous intracranial surgery. 12. Patients who are currently under DBS therapy or have implanted any kind of stimulator already. 13. Patients with aneurysm clips. 14. Patients with cochlear implants. 15. Patients with planned diathermy. 16. Persons who are in a relationship of dependence/employment with the sponsor or the investigator. 17. Simultaneous participation or previous participation within 30 days prior to start of screening in a clinical trial involving investigational medicinal product(s) or investigational medical device(s).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Asberg Depression Rating Scale (MADRS) total score | 16 weeks after surgery | Primary outcome (Efficacy). MADRS is an established instrument to rate symptoms of depression. The questionnaire includes questions on the following symptoms 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts Each of the 10 items yields a score of 0 to 6. These item scores are summed up to yield a total score. The range of the total score is thus 0 to 60; higher total scores indicate more severe depressive symptoms. Usual cutoff points are: 0 to 6 - normal/symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; \>34 - severe depression |
| Time to Montgomery-Asberg Depression Rating Scale (MADRS) augmentation of >5 points or clinical worsening in two consecutive visits after DBS termination | Up to 3 months | Primary outcome in 2nd stage; Description MADRS: see above. |
| Assessment of (Serious) Adverse Events related to Investigational Medical Device and / or surgical procedures | From IMD implantation until the end of study; assessed up to 77 weeks | Primary outcome (Safety); (Serious) adverse events seen will be reported using standard descriptive statistical methods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Depression Rating Scale (HDRS-28) total score | 16 weeks after surgery | HDRS is an established instrument to rate symptoms of depression. Different versions exist, using between 17 and 29 items. In this study, the 28-item version (HDRS-28) is used. The patient is rated by a clinician, items are scored either on a 3-point or 5-point Likert-type scale. Single item scores are summed up to yield a total score. The total score ranges from 0 to 85; a higher total score indicates more severe depressive symptoms. |
| Clinical Global Impression Score (CGI) total score | 16 weeks after surgery | The CGI is a scale that measures the global severity of illness, the global improvement relative to the beginning of the study as well as the therapeutic effect and adverse reactions, score ranges from 0 to 7 for severity of illness and global improvement, a higher score indicates more severe symptoms and a worsening of symptoms; score ranges from 0 to 8 for the efficacy index, 0 means that the efficacy can't be evaluated, a score of 2 means best efficacy while a score of 8 means no therapeutic effect and more adverse reactions |
| Global Assessment of Functioning (GAF) total score | 16 weeks after surgery | Score ranges from 100 (high functioning) to 1 (severly impaired) |
| Beck Depression Inventory (BDI-II) total score | 16 weeks after surgery | Score ranges from 0 to 63; a higher total score indicates more severe depressive symptoms |
| 36-Item Short Form Health Survey (SF-36) total score | 16 weeks after surgery | Health-related quality of life questionnaire; 8 subscales: General health perceptions, physical functioning, role limitations due to physical problems, bodily pain, vitality, general mental health, role limitations due to emotional problems, social functioning. The score in each subscale ranges from 0 to 100; subscores add up to two total scores, "physical health" and "mental health", each with a score range of 0-400. Higher scores indicate better health-related quality of life. |
| Change over time in HDRS total score after DBS surgery with DB stimulation OFF compared to stimulation ON | assessed weekly for 16 weeks after surgery | HDRS: see above |
| Change over time in CGI total score after DBS surgery with DB stimulation OFF compared to stimulation ON | assessed weekly for 16 weeks after surgery | CGI: see above |
| Change over time in GAF total score after DBS surgery with DB stimulation OFF compared to stimulation ON | assessed weekly for 16 weeks after surgery | GAF: see above |
| Change over time in BDI-II total score after DBS surgery with DB stimulation OFF compared to stimulation ON | assessed weekly for 16 weeks after surgery | BDI-II: see above |
| Change over time in SF-36 total score after DBS surgery with DB stimulation OFF compared to stimulation ON | assessed weekly for 16 weeks after surgery | SF-36: see above |
| Neuropsychological Assessments: Rey Complex Figure Test (CFT) | at 4 months after implantation | Score range 0-36, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: d2 concentration test (d2) | at 4 months after implantation | Higher scores indicate better cognitive performance (total of right answers minus errors) |
| Neuropsychological Assessments: 5-Point-Test | at 4 months after implantation | Score range 0-35, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: Wechsler Adult Intelligence Scale (WAIS) (vocabulary, similarities) | at 4 months after implantation | Score range "vocabulary": 0-32, Score range "finding similarities": 0-32, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: Mini-Mental-Status-Test (MMST) | at 4 months after implantation | Score range 0-30, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: Multiple-Choice Vocabulary Intelligence Test (MWT-B) | at 4 months after implantation | Score range 0-37, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: Rey Visual Design Learning Test (RVDLT) | at 4 months after implantation | Score range 0-75, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: Word Fluency Test | at 4 months after implantation | No maximum scores, patient has two minutes to produce answers, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: Stroop-Test | at 4 months after implantation | Time in s, low scores (less seconds) indicate better cognitive performance |
| Neuropsychological Assessments: Test for Attentional Performance (TAP) | at 4 months after implantation | Reaction times as well as correct or false responses and omissions are measured, higher cognitive performance is indicated by fast responses, few errors and high no. of correct responses |
| Neuropsychological Assessments: Trail-Making Test (TMT) | at 4 months after implantation | Time in s, low scores (less seconds) indicate better cognitive performance |
| Neuropsychological Assessments: Verbal Memory and Learning Ability Test | at 4 months after implantation | Score range 0-75, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: Hopper Visual Organization Test (VOT) | at 4 months after implantation | Score range 0-30, higher scores indicate better cognitive performance |
| Neuropsychological Assessments: Digit-Span and Block-Span Test | at 4 months after implantation | Score range 0-12 for each of for dimensions: Digit span forward, digit span backward, block span forward, block span backward. Higher scores indicate better cognitive performance |
| MADRS total score during long-term follow-up compared to baseline | at 12 months stimulation | MADRS: see above |
| HDRS total score during long-term follow-up compared to baseline | at 12 months stimulation | see above |
| CGI total score | at 6 and 12 months DB stimulation compared to baseline | see above |
| GAF total score | at 6 and 12 months DB stimulation compared to baseline | see above |
| BDI-II total score | at 6 and 12 months DB stimulation compared to baseline | see above |
| SF-36 total score | at 6 and 12 months DB stimulation compared to baseline | see above |
| Incidence of relapse into clinical depression after tapering down of DBS | From discontinuation of DBS until the date of first documented relapse, assessed up to 12 weeks | The incidence of relapse into clinical depression after discontinuation of DBS will be assessed. |
| Pattern of metabolic activity as measured by FDG-PET at 1 week and 4 months after implantation compared to baseline | at 1 week and 4 months after implantation compared to baseline | Change of metabolic activity in the prefrontal and orbitofrontal cortex as well as in subcortical regions (nucl. accumbens, amygdala) (exploratory endpoint) |
Countries
France, Germany
Contacts
PRINCIPAL_INVESTIGATORJuan Carlos Baldermann-Weiß, PD Dr.
University Hospital Freiburg
Outcome results
None listed