Effects of Deep Brain Stimulation in Treatment Resistant Major Depression

Study Overview
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Brief Summary
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The investigators will investigate in a sham controlled design antidepressant effects and safety of DBS to the superolateral branch of the main medial forebrain bundle (slMFB).

Detailed Description
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The target point for DBS in major depression disorder is located lateral to the ventral tegmental area (VTA) in the midbrain at the branching point of the superolateral branch (slMFB) from the main medial forebrain bundle (MFB). The exact stimulation coordinates are: MNI152 coordinates: left: x(lat.)=-5, y(ap)=-14, z(vert.)=-8 right: x(lat.)=5, y(ap)=-14, z(vert.)=-9 MCP coordinates: eft: x(lat.)=-6, y(ap)=-1, z(vert.)=-6 right: x(lat.)=4, y(ap)=-1, z(vert.)=-7 All coordinates refer to the MNI152 brain. Legend: slMFB = superolateral branch of medial forebrain bundle, MNI152=Montreal Neurologic Institute brain 152 coordinates, MCP = mid-commissural point coordinates, lat. = lateral, ap= antero-posterior, vert. = vertical. More information can be found at: http://goo.gl/n9sWV In addition to the described intervention, we will record EEG activity within the implanted regions during cognitive paradigms (Fell and Axmacher, Nat Rev Neurosci 2011). Specifically, we will investigate the neural mechanisms underlying classification learning, working memory and exploration of rewarded spatial locations and explore oscillatory responses following stimulation of the target regions. These experimental paradigms will be conducted on the first day after electrode implantation.

Official Title
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Assessment of Efficacy, Safety and Effects on Quality of Life of Deep Brain Stimulation to the Medial Forebrain Bundle in Patients With Treatment Resistant Major Depression (FORESEE: FOREbrain Stimulation dEprEssion)

Conditions
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Major Depression

Intervention / Treatment
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* Device: DBS
* Device: No Stimulation (Sham)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Major depression (MD), severe, unipolar type German mother tongue Hamilton Depression Rating Scale (HDRS24) score of > 20 Global Assessment of Function (GAF) score of < 45 At least 4 episodes of MD or chronic episode > 2 years > 5 years after first episode of MD Failure to respond to adequate trials (>5 weeks at the maximum recommended or tolerated dose) of primary antidepressants from at least 3 different classes; adequate trials (>3 weeks at the usually recommended or maximum tolerated dose) of augmentation/combination of a primary antidepressant using at least 2 different augmenting/combination agents (lithium, T3, stimulants, neuroleptics, anticonvulsants, buspirone, or a second primary antidepressant); an adequate trial of electroconvulsive therapy [ECT] (>6 bilateral treatments) and; an adequate trial of individual psychotherapy (>20 sessions with an experienced psychotherapist). Able to give written informed consent No medical comorbidity Drug free or on stable drug regimen at least 6 weeks before study entry Exclusion Criteria: Current or past nonaffective 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 surgical contraindications to undergoing DBS Current or unstably remitted substance abuse (aside from nicotine) Pregnancy and women of childbearing age not using effective contraception History of severe personality disorder

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sham then Stimulation<br> | Device: DBS<br>* 130Hz, 90us pulsewidth, 4V Amplitude<br>* Other names: INS;Device: No Stimulation (Sham)<br>* 130Hz, 90us pulsewidth, 0V Amplitude<br>* Other names: INS;|
| Experimental: Stimulation then Sham<br> | Device: DBS<br>* 130Hz, 90us pulsewidth, 4V Amplitude<br>* Other names: INS;Device: No Stimulation (Sham)<br>* 130Hz, 90us pulsewidth, 0V Amplitude<br>* Other names: INS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depression Severity assessed with Montgomery Asberg Depression Scale (MADRS) | Change in MADRS after 12 months as compared to mean baseline score. MADRS is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. It is used as an adjunct to the Hamilton Rating Scale for Depression (HAMD) and more sensitive to the changes in depression than the Hamilton Scale is. MADRS will be rated 3 times for baseline assessment, weekly during parameter optimization and monthly during follow-up. Reduction compared to baseline will be assessed after 12 months of DBS. | 12 month after DBS stimulation onset | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depression Severity rated with Hamilton Depression Rating Scale (HDRS24) | The Hamilton Rating Scale for Depression (HRSD), also known as the Hamilton Depression Rating Scale (HDRS) or abbreviated to HAM-D, is a multiple choice questionnaire that clinicians may use to rate the severity of a patient's major depression. The questionnaire rates the severity of symptoms observed in depression such as low mood, insomnia, agitation, anxiety and weight loss. The questionnaire is presently one of the most commonly used scales for rating depression in medical research. Measures will be taken at same time points as primary outcome measure. | 12 month after DBS stimulation onset | 
| Adverse Event Schedule | Adverse events will be recorded during the study using a structured questionnaire. All possible AEs are assessed in severity, duration and actions taken. 12 months after stimulation onset results will be compiled and rated as being due to the surgical procedure, device, or stimulation. SAEs will be discussed individually if a modification of study protocol is required. | 12 month after DBS stimulation onset | 
| Comprehensive neuropsychological test battery |  | 12 month after DBS stimulation onset |