Deep Brain Stimulation (DBS) Therapy for Treatment Resistant Depression

Study Design: Subjects will be ten patients with MDD identified via the Structured Clinical
Interview for DSM-IV, manifesting a current major depressive episode of disabling severity,
refractory to prolonged treatment trials with conventional medication, electro-convulsive
therapy (ECT) and psychotherapy. A marked impact of depression on their health and functional
status will be evidenced by major impairment in functioning or potentially severe medical
outcomes (repeated hospitalizations, serious suicidal or other self-injurious behavior). They
will be recruited from individuals currently seen at our facility or referred by
psychiatrists in the community. Patients will be initially screened by a comprehensive review
of their psychiatric history, obtained by interview of the patient, family and treating
psychiatrist and/or psychologist, as well as by obtaining and reviewing all available records
of previous psychiatric treatment. The available generally-accepted alternative treatments
for depression are pharmacologic therapy, psychotherapy, and ECT. Failed trials of multiple
proven pharmacologic treatments, an adequate course of psychotherapy, and an adequate course
of bilateral ECT (or inability to tolerate an adequate ECT trial) are inclusion criteria for
all candidates who are considered for this study. However, as alternatives to participation
in this study, candidates may undertake additional trials of potentially beneficial novel
combinations of medication and psychotherapy, or they may undertake trials of novel
interventions lacking definitive evidence of efficacy in severe depression (e.g., light
therapy, herbal therapy, transcranial magnetic stimulation, vagal nerve stimulation). The
protocol was designed to include four phases. All patients will enter these phases in the
same sequence. The experimental design is illustrated in the timeline in Figure 1. Surgical
implantation will be followed by: 1) Baseline Phase (a 1 month period with no stimulation);
2) Variable Staggered Phase (blinded stimulation onset starting from 1 month to 3 months post
implant, with optimal parameter determination during this time ; 3) Initial Chronic Phase
(blinded bilateral stimulation, lasting at least three months) (see below); 4) Continuation
Phase (unblinded active bilateral or unilateral stimulation to maximize clinical response)
Protocol overview and design: We propose a clinical study of medial forebrain bundle DBS as a
treatment in 10 patients with treatment refractory depression (TRD). Data from the University
of Bonn indicates that surgical lesions of the medical forebrain bundle can produce
therapeutic benefits in patients with depressive disorders, and suggest that DBS at the same
site may also reduce symptomatology in these TRD patients (Schaepfer, 2013). Depression
affects up to 10% of the US population and of those at least 10-15% do not benefit from
therapies hence why we must explore new treatments. The Activa® systems manufactured by
Medtronic Neurological will be used in this study. Those identified as TRD patients will then
be enrolled in a clinical pilot study investigating DBS, targeting the MFB.

Inclusion Criteria:

1. Major Depression Disorder (MDD) diagnosed by Structured Clinical Interview for DSM-IV
(SCID I/DSM-IV), judged to be of disabling severity.

2. Age 22 - 65 years.

3. 24-item Hamilton Depression Rating Scale (HDRS) score of at least 21 on the first 17
items

4. Global Assessment of Function (GAF) score of 45 or less.

5. A recurrent (equal or >4 episodes) or chronic (episode duration equal or higher >2
years) course AND a minimum of 5 years since the onset of the first depressive
episode. Major impairment in functioning or potentially severe medical outcomes
(repeated hospitalizations, serious suicidal or other self-injurious behavior).

6. Failure to respond to: 6.1. Adequate trials (equal or >6 weeks at the maximum
recommended or tolerated dose) of primary antidepressants from at least 3 different
classes AND; 6.2. adequate trials ( equal>4 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) AND; 6.3
An adequate trial of ECT (>6 bilateral treatments), or inability to tolerate an
adequate ECT trial, AND; 6.4 An adequate trial of individual psychotherapy (>20
sessions with an experienced psychotherapist).

7. Able to comply with the operational and administrative requirements of participation
in the study.

8. Able to give written informed consent

9. On a stable drug regimen of psychotropic medication for at least 6 weeks at the time
of entry into the study.

10. Good general health. No changes in medication treatment during participation in study.

Exclusion Criteria:

1. Current or past non-affective psychotic disorder, Bipolar Disorder, Schizophrenia, or
Schizoaffective disorder. Patients who suffer from generalized anxiety disorder will
be permitted to participate as long as MDD is the primary clinical diagnosis.

2. Any current clinically significant neurological disorder, including dementia or
medical illness affecting brain function.

3. Any clinically significant abnormality on preoperative magnetic resonance imaging
(MRI).

4. Any previous surgery to destroy the region of the brain that will be the target of
treatment.

5. Any surgical contraindications to undergoing DBS, including labeled contraindications
for DBS and/or inability to undergo presurgical MRI (cardiac pacemaker, implantable
defibrillator or other implantable stimulator, pregnancy, metal in body, severe
claustrophobia), infection, coagulopathy, inability to undergo an awake operation,
significant cardiac or other medical risk factors for surgery.

6. Refusal of an adequate trial of ECT.

7. History of stimulation intolerance in any area of the body.

8. Current or unstably remitted substance abuse or dependence. No alcohol and/or
substance abuse or dependence in the past 6 months.

9. Pregnancy and women of childbearing age not using effective contraception.
Double-barrier method is required.

10. History of severe personality disorder, where, based on the judgment of the
investigators, the personality disorder will interfere with the patient's ability to
complete the follow-up protocol, e.g. borderline personality disorder.

11. Imminent risk of suicide

12. Participation in another drug, device, or biologics trial within the preceding 30 days

13. Presence of a condition requiring routine MRIs.

14. Presence of a condition requiring diathermy.

15. Subject is on anticoagulant medication.

16. Not able to comply with the operational and administrative requirements of
participation in the study (based on the judgment of the investigators).

17. Terminal illness associated with expected survival of <12 months.