Business reasons

This study is designed as a prospective, multi-centered, double-blind, randomized, controlled 12-month pivotal study to evaluate the safety and efficacy of the ANS Libra® Deep Brain Stimulation System for patients with major depressive disorder who have failed at least 4 treatments in the current episode. The primary outcome assessment will occur at 6 months: however, all patients will be followed for 1 year. A total of 201 patients will be randomized from up to 20 sites.

Each potential patient will be pre-screened according to the inclusion/exclusion criteria. A narrative of what study participation entails, will be used to educate potential participants on study requirements. Prior to on-site baseline evaluations, the patient will sign the informed consent. Patients will then undergo 3 baseline evaluations, with each of these evaluations to occur no less than 2 weeks apart from each other. The first 2 baseline visit evaluations will be performed by separate psychiatrists in order to confirm the patient's diagnosis. All patients will be scheduled for surgery, to occur no less than two weeks and no more than 1 month after final baseline evaluation, to implant the ANS Libra® Deep Brain Stimulation system. After device implantation, patients will be randomly assigned to 1 of 2 groups in a 2:1 ratio (Active Treatment Group & Control Group).

After system implant (Week 0), the patient will return to clinic approximately 2 weeks after surgery for evaluation and treatment randomization into either Group 1 or Group 2 (Group 1 = Active Treatment Group; Group 2 = Control Group). Patient will then return to clinic for subsequent evaluations at 2 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, and 1 year post system implantation.

Inclusion Criteria:

1. Men and women (non-pregnant) age is 21-70 years;
2. Diagnosed with non-psychotic major depressive disorder, single or recurrent episode by DSM-IV-TR criteria derived from the MINI;
3. First episode onset before age 45;
4. Current episode ≥ 12 months duration;
5. In the current episode: Documented resistance (i.e.persistence of the major depressive episode) to a minimum of 4 adequate depression treatments from at least 3 different treatment categories (e.g. SSRI's, SNRI's, TCA's, MAO inhibitors, Mirtazipine, Nefazodone, Trazodone, Bupropion, lithium augmentation, thyroid augmentation, ECT); Adequacy of treatments as defined by a score of at least 3 according to the amended Antidepressant Treatment History Form (ATHF) criteria;
6. In Lifetime: Received a course of psychotherapy for depression;
7. Montgomery Asberg Depression Rating Scale (MADRS) of ≥ 22 at 3 separate baseline visits, rated by 2 separate psychiatrists, Baseline 2 and Baseline 3 MADRS scores cannot be separated by > 6 weeks and cannot improve ≥ 20%;
8. Global Assessment of Function, score <50;
9. Modified mini-mental state examination (MMSE) score ≥24;
10. No change in current antidepressant medication regimen or medication free ≥4 weeks prior to study entry (with exception to sleep, cholesterol, blood pressure, sexual dysfunction, non-migraine headache medication, or medication for other medical reasons not related to depression, in which changes to dose or type will be allowed during course of study);
11. Able to give informed consent in accordance with institutional policies;
12. Able to comply with all testing and follow-up requirements as defined by the study protocol;
13. Must be determined medically stable by surgeon, to undergo deep brain stimulation surgical procedure.
14. Must have platelet count, PT and PTT within normal limits of the laboratory.
15. During last 6 months in the current episode documented treatment under the care of a licensed psychiatrist/psychologist.

Exclusion Criteria:

1. A diagnosis of a bipolar I or bipolar II disorder by DSM-IV-TR criteria, derived from the MINI;
2. Meets criteria for borderline or antisocial personality disorder in the last 12 months by DSM-IV-TR criteria, derived from the Cluster B Personality Disorders Sections 301.7 - 301.83, and screened via SCID-II at Baseline visit;
3. In the current depressive episode, has been diagnosed with General Anxiety Disorder (GAD) - as defined by the DSM-IV-TR, and GAD is the primary diagnosis;
4. Has an intracranial Central Nervous System (CNS) disease that impairs motor, sensory or cognitive function or that requires intermittent or chronic medication (e.g., Parkinson's Disease, chronic migraine, stroke, Huntington's, head trauma, etc.) with exception to non-migraine headaches;
5. Has been diagnosed with fibromyalgia or has a current condition which requires chronic pain narcotic usage (e.g. morphine, methadone);
6. Has been currently diagnosed with chronic fatigue syndrome;
7. Substantial suicidal risk as defined by (1) MADRS item 10 score of 5 or 6, (2) a current plan and intent,(3) clinician judgment that there is a clear immediate intent for self-harm, (4) more than 3 suicide attempts within the last 12 months;
8. Co-morbid obsessive compulsive disorder, posttraumatic stress disorder, panic disorder, bulimia or anorexia nervosa if previously present, must be in remission for 6 months as defined by DSM-IV-TR criteria, derived from the MINI;
9. Alcohol, medication, or illegal substance dependence or abuse within last 12 months derived from the MINI;
10. Diagnosis of sleep apnea confirmed by a sleep test that is not adequately treated;
11. Advanced cardiovascular disease which renders anesthesia and surgery as unsafe as determined by neurosurgeon;
12. Clinically relevant abnormality (e.g. tumor or growth) on study MRI;
13. Has cardiac pacemaker/defibrillator or other implanted active stimulator;
14. Has a medical condition requiring a repetitive MRI body scan;
15. Requires chemotherapy for the treatment of malignancy or requiring chronic oral or intravenous (immunosuppressive or) steroid therapy;
16. Is unable to comply with study visit schedule and timeline;
17. Past ablative or relevant intracranial surgery;
18. A female lactating or of child bearing potential, with a positive pregnancy test or not using adequate contraception;
19. Lifetime psychotic disorders, schizophrenia, or schizoaffective disorder defined by DSM-IV-TR;
20. Psychotic features in current depressive episode as diagnosed by DSM-IV-TR criteria;
21. Other medical conditions likely to require hospitalization within the next year;
22. Received ECT within 3 months prior to enrollment, or requires ECT for the duration of the study;
23. Has a history of epilepsy or history of status epilepticus;
24. Plans to use diathermy;
25. Has any metallic implants such as aneurysm clips or cochlear implants;
26. Currently participating in another investigational device, drug or surgical trial