Controlled Randomized Clinical Trial to Assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients With Treatment Resistant Major Depression
Overview
- Phase
- Not Applicable
- Intervention
- Vercise GEVIA deep brain stimulation (DBS) system
- Conditions
- Treatment-resistant Depression
- Sponsor
- University Hospital Freiburg
- Enrollment
- 46
- Locations
- 4
- Primary Endpoint
- Montgomery-Asberg Depression Rating Scale (MADRS) total score
- Status
- Completed
- Last Updated
- 4 days ago
Overview
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.
Investigators
Juan Carlos Baldermann
Principal Investigator, Head of Interventional Biological Psychiatry
University Hospital Freiburg
Eligibility Criteria
Inclusion Criteria
- •Major depression (MD), severe, unipolar, or bipolar in an acute depression episode.
- •German mother tongue or fluent.
- •Male or female patients ≥20 and ≤75 years.
- •Hamilton Depression Rating Scale (HDRS-28) score of \>
- •Global Assessment of Function (GAF) score of \<
- •At least 4 episodes of depression or one chronic episode \>2 years.
- •Failure to respond to
- •adequate trials of primary antidepressants from at least 3 different classes (\>5 weeks at the maximum recommended or tolerated dose) and
- •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
- •an adequate trial of electroconvulsive therapy (ECT) (\>6 treatments) and an adequate trial of individual psychotherapy (\>20 sessions with an experienced psychotherapist).
Exclusion Criteria
- •Current or past non-affective psychotic disorder.
- •Any current clinically significant neurological disorder or medical illness affecting brain function, other than motor tics or Gilles de la Tourette syndrome.
- •Any clinically significant abnormality on preoperative magnetic resonance imaging (MRI), any contraindications to perform a planned MRI to visualize the slMFB.
- •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).
- •Current or unstably remitted substance abuse (aside from nicotine).
- •Pregnancy, women of childbearing age not using effective contraception and breast feeding women.
- •History of severe personality disorder.
- •Acute suicidal ideation.
- •Patients with advanced stage cardiovascular disease.
- •Patients under immunosuppressive or chemo therapy because of malignant disease.
Arms & Interventions
Group A: DBS onset in week 1
Implantation of Vercise GEVIA deep brain stimulation (DBS) system. DBS onset in week 1. 2ND STAGE: After 6 months DBS ON, patients will be assessed whether they are responders or non-responders. In the subgroup of eligible responders, patients will be randomized to either DBS OFF\* (for max. 3 months) or continued DBS for another 6 months. \*DBS OFF until worsening of clinical depression, event (defined as \> 5 points augmentation in MADRS in two consecutive visits) or for a maximum of 3 months. After DBS OFF, re-onset of DBS will be performed, followed by 6 months continuous DBS. Non-responders will also receive another 6 months DBS therapy in the 2nd stage. At sites other than Freiburg/Bonn, the 2nd stage consists of 6 months DBS therapy only.
Intervention: Vercise GEVIA deep brain stimulation (DBS) system
Group B: DBS off, followed by DBS onset in week 17
Implantation of Vercise GEVIA deep brain stimulation (DBS) system. 4 months OFF after implantation followed by DBS onset in first week of month 5. 2ND STAGE: See group A.
Intervention: Vercise GEVIA deep brain stimulation (DBS) system
Outcomes
Primary Outcomes
Montgomery-Asberg Depression Rating Scale (MADRS) total score
Time Frame: 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
Time Frame: 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
Time Frame: 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 Outcomes
- CGI total score(at 6 and 12 months DB stimulation compared to baseline)
- 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)
- Global Assessment of Functioning (GAF) total score(16 weeks after surgery)
- 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)
- Neuropsychological Assessments: 5-Point-Test(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Multiple-Choice Vocabulary Intelligence Test (MWT-B)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Stroop-Test(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Beck Depression Inventory (BDI-II) total score(16 weeks after surgery)
- 36-Item Short Form Health Survey (SF-36) total score(16 weeks after surgery)
- 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)
- Neuropsychological Assessments: Rey Complex Figure Test (CFT)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Word Fluency Test(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- 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)
- Neuropsychological Assessments: Rey Visual Design Learning Test (RVDLT)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Test for Attentional Performance (TAP)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- BDI-II total score(at 6 and 12 months DB stimulation compared to baseline)
- 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)
- Hamilton Depression Rating Scale (HDRS-28) total score(16 weeks after surgery)
- Clinical Global Impression Score (CGI) total score(16 weeks after surgery)
- 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)
- Neuropsychological Assessments: d2 concentration test (d2)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Trail-Making Test (TMT)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- HDRS total score during long-term follow-up compared to baseline(at 12 months stimulation)
- GAF total score(at 6 and 12 months DB stimulation compared to baseline)
- 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)
- Neuropsychological Assessments: Wechsler Adult Intelligence Scale (WAIS) (vocabulary, similarities)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Mini-Mental-Status-Test (MMST)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Verbal Memory and Learning Ability Test(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Hopper Visual Organization Test (VOT)(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- Neuropsychological Assessments: Digit-Span and Block-Span Test(at 6 months DBS compared to baseline and at end of the study compared to baseline, assessed up to 77 weeks)
- MADRS total score during long-term follow-up compared to baseline(at 12 months stimulation)
- SF-36 total score(at 6 and 12 months DB stimulation compared to baseline)
- Neuropsychological Assessments: Rey Complex Figure Test (CFT)(at 4 months after implantation)
- Neuropsychological Assessments: d2 concentration test (d2)(at 4 months after implantation)
- Neuropsychological Assessments: 5-Point-Test(at 4 months after implantation)
- Neuropsychological Assessments: Wechsler Adult Intelligence Scale (WAIS) (vocabulary, similarities)(at 4 months after implantation)
- Neuropsychological Assessments: Mini-Mental-Status-Test (MMST)(at 4 months after implantation)
- Neuropsychological Assessments: Multiple-Choice Vocabulary Intelligence Test (MWT-B)(at 4 months after implantation)
- Neuropsychological Assessments: Rey Visual Design Learning Test (RVDLT)(at 4 months after implantation)
- Neuropsychological Assessments: Word Fluency Test(at 4 months after implantation)
- Neuropsychological Assessments: Stroop-Test(at 4 months after implantation)
- Neuropsychological Assessments: Test for Attentional Performance (TAP)(at 4 months after implantation)
- Neuropsychological Assessments: Trail-Making Test (TMT)(at 4 months after implantation)
- Neuropsychological Assessments: Verbal Memory and Learning Ability Test(at 4 months after implantation)
- Neuropsychological Assessments: Hopper Visual Organization Test (VOT)(at 4 months after implantation)
- Neuropsychological Assessments: Digit-Span and Block-Span Test(at 4 months after implantation)