Feasibility, Safety and Efficacy of Deep Brain Stimulation for Depression

This protocol proposes a pilot/feasibility clinical study of therapeutic benefits of ventral
capsule/ventral striatum deep brain stimulation (DBS) as a treatment in ten patients with
intractable major depression (MD). Conservative estimates place MD's prevalence at 2.6% to
5.5% in men and 6.0% to 11.8% in women. Most conservative studies estimate a 20% complete
refractoriness to medical and psychotherapeutic regimens. Given the prevalence of major
depression in the general population, over 3.5 million Americans would be expected to
manifest refractory illness if all those with depression received treatment. Study subjects
will have MD of disabling severity, intractable to prolonged treatment attempts with
conventional medication and pschotherapies. They must also have had electroconvulsive
therapy. These refractory patients would be candidates for a destructive/lesioning brain
surgery such as a radiofrequency cingulotomy.

These MD patients are analogous to medically intractable Parkinson's disease and tremor
patients who until recently underwent similar destructive surgeries such as a pallidotomy or
thalamotomy. The use of DBS technology with its inherent advantage of being fully reversible
and adjustable has become standard of care for these disabled patients. Studies have
demonstrated improved safety and efficacy of DBS over lesioning.

Recently, DBS technology has been employed in the lesioning target of the anterior limb of
the internal capsule for OCD. These preliminary studies in Europe and now the US, are
demonstrating improved outcomes for refractory OCD patients with regard to their OC symptoms
as well as depressed mood. This amelioration of mood provides the basis on which anterior
internal capsule DBS may help major depression patients.

Based on this rationale, we believe that DBS is a viable therapeutic surgical option in this
group of severely ill MD patients. The standard DBS stereotactic surgical techniques
employed by the CCF team in hundreds of movement disorder patients will be used. The DBS
electrodes will be implanted bilaterally in the anterior limb of the internal capsule and
connected subcutaneously to subclavicular programmable pulse generators.

Inclusion Criteria:

- Major depression, severe, unipolar type, diagnosed by Structured Clinical Interview
for DSM-IV (SCID-IV), judged to be of disabling severity

- 24-item Hamilton Depression Rating Scale (HDRS) score of at least 21

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

- A recurrent (>4 episodes) or chronic (episode duration >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).

- Failure to respond to:

- adequate trials (>6 weeks at the maximum recommended or tolerated dose) of
primary antidepressants from at least 3 different classes and;

- adequate trials (>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;

- an adequate trial of ECT (>6 bilateral treatments) and;

- an adequate trial of individual psychotherapy (>20 sessions with an experienced
psychotherapist).

- Age 18 - 55 years.

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

- Able to give written informed consent.

- Either drug-free or on a stable drug regimen for at least 6 weeks at the time of
entry into the study.

- Good general health.

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

- Current or unstably remitted substance abuse.

- Pregnancy and women of childbearing age not using effective contraception.

- History of severe personality disorder.

- Imminent risk of suicide (based on the judgment of the investigators).

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