Efficacy Study of Deep Brain Stimulation in Patients With Treatment Resistant Major Depression

University Hospital Freiburg46 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Treatment-resistant Depression

Interventions

Vercise GEVIA deep brain stimulation (DBS) systemDEVICE

DBS to the superolateral branch of the Medial Forebrain Bundle (slMFB)

Eligibility

Sex: ALLMin age: 20 YearsMax age: 75 Years

Medical Language ↔ Plain English

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).

Locations (2)

Université Grenoble Alpes

Grenoble, France

University Hospital Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Outcomes

Primary Outcomes

Montgomery-Asberg Depression Rating Scale (MADRS) total score

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 frame: 16 weeks after surgery

Time to Montgomery-Asberg Depression Rating Scale (MADRS) augmentation of >5 points or clinical worsening in two consecutive visits after DBS termination

Primary outcome in 2nd stage; Description MADRS: see above.

Time frame: Up to 3 months

Assessment of (Serious) Adverse Events related to Investigational Medical Device and / or surgical procedures

Primary outcome (Safety); (Serious) adverse events seen will be reported using standard descriptive statistical methods.

Time frame: From IMD implantation until the end of study; assessed up to 77 weeks

Secondary Outcomes

Hamilton Depression Rating Scale (HDRS-28) total score

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.

Time frame: 16 weeks after surgery

Data from ClinicalTrials.gov

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Clinical Global Impression Score (CGI) total score

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

Time frame: 16 weeks after surgery

Global Assessment of Functioning (GAF) total score

Score ranges from 100 (high functioning) to 1 (severly impaired)

Time frame: 16 weeks after surgery

Beck Depression Inventory (BDI-II) total score

Score ranges from 0 to 63; a higher total score indicates more severe depressive symptoms

Time frame: 16 weeks after surgery

36-Item Short Form Health Survey (SF-36) total score

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.

Time frame: 16 weeks after surgery

Change over time in HDRS total score after DBS surgery with DB stimulation OFF compared to stimulation ON

HDRS: see above

Time frame: assessed weekly for 16 weeks after surgery

Change over time in CGI total score after DBS surgery with DB stimulation OFF compared to stimulation ON

CGI: see above

Time frame: assessed weekly for 16 weeks after surgery

Change over time in GAF total score after DBS surgery with DB stimulation OFF compared to stimulation ON

GAF: see above

Time frame: assessed weekly for 16 weeks after surgery

Change over time in BDI-II total score after DBS surgery with DB stimulation OFF compared to stimulation ON

BDI-II: see above

Time frame: assessed weekly for 16 weeks after surgery

Change over time in SF-36 total score after DBS surgery with DB stimulation OFF compared to stimulation ON

SF-36: see above

Time frame: assessed weekly for 16 weeks after surgery

Neuropsychological Assessments: Rey Complex Figure Test (CFT)

Score range 0-36, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: d2 concentration test (d2)

Higher scores indicate better cognitive performance (total of right answers minus errors)

Time frame: at 4 months after implantation

Neuropsychological Assessments: 5-Point-Test

Score range 0-35, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Wechsler Adult Intelligence Scale (WAIS) (vocabulary, similarities)

Score range "vocabulary": 0-32, Score range "finding similarities": 0-32, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Mini-Mental-Status-Test (MMST)

Score range 0-30, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Multiple-Choice Vocabulary Intelligence Test (MWT-B)

Score range 0-37, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Rey Visual Design Learning Test (RVDLT)

Score range 0-75, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Word Fluency Test

No maximum scores, patient has two minutes to produce answers, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Stroop-Test

Time in s, low scores (less seconds) indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Test for Attentional Performance (TAP)

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

Time frame: at 4 months after implantation

Neuropsychological Assessments: Trail-Making Test (TMT)

Time in s, low scores (less seconds) indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Verbal Memory and Learning Ability Test

Score range 0-75, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Hopper Visual Organization Test (VOT)

Score range 0-30, higher scores indicate better cognitive performance

Time frame: at 4 months after implantation

Neuropsychological Assessments: Digit-Span and Block-Span Test

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

Time frame: at 4 months after implantation

MADRS total score during long-term follow-up compared to baseline

MADRS: see above

Time frame: at 12 months stimulation

HDRS total score during long-term follow-up compared to baseline

see above

Time frame: at 12 months stimulation

CGI total score

see above

Time frame: at 6 and 12 months DB stimulation compared to baseline

GAF total score

see above

Time frame: at 6 and 12 months DB stimulation compared to baseline

BDI-II total score

see above

Time frame: at 6 and 12 months DB stimulation compared to baseline

SF-36 total score

see above

Time frame: at 6 and 12 months DB stimulation compared to baseline

Neuropsychological Assessments: Rey Complex Figure Test (CFT)

see above