Long Term Follow-up of Deep Brain Stimulation for Treatment-Resistant Depression

The U.S. lifetime prevalence of major depressive disorder (MDD) is 17%. A number of
treatments are available for depression including medications, psychotherapy and various
somatic treatments. Unfortunately, up to two-thirds of patients remain symptomatic following
first-line treatment and a third fail to achieve remission (defined as full resolution of
depressive symptoms) after four established treatments; approximately 10%-20% of depressed
patients may show virtually no improvement despite multiple, often aggressive treatments.
Thus, a conservative estimate places the U.S. prevalence of treatment-resistant depression
(TRD) at 1%-3%. TRD has a high risk of suicide, is a major cause of disability and is
responsible for doubling of overall health care costs.

For patients with TRD there are limited evidence-based treatment options. Transcranial
magnetic stimulation (TMS) may have efficacy for patients that have failed no more than one
antidepressant medication 10-12, but response and remission rates are relatively low (under
30% and 20% respectively). Vagus nerve stimulation (VNS) may have efficacy in patients that
have failed 4-6 antidepressant treatments but long-term response and remission rates are
again low (about 20% and 10% respectively). Electroconvulsive therapy(ECT) can be effective
in TRD patients with remission rates of 50%-60%. However, more than 70% of TRD patients will
relapse within 6 months following a successful acute treatment course. For patients that have
failed ECT, there are no evidence-based treatment options. Therefore, there is great need for
novel treatment approaches for TRD.

Prior clinical trials have shown that SCC DBS has the potential to be a valuable treatment
option for patients with TRD. Further developing this treatment will involve confirming its
effectiveness and identifying ways to optimize its use. In this study the investigators
intend to test the safety and efficacy of chronic SCC DBS as a treatment for TRD and compare
the safety and efficacy of left-sided versus right-sided stimulation using a double-blind,
randomized, cross-over design.

Inclusion Criteria:

- Have received DBS for TRD

- Ability to provide written informed consent

- Willing to comply with all necessary study visits

Exclusion Criteria:

- Significant cerebrovascular risk factors or a previous stroke, documented major head
trauma or neurodegenerative disorder.

- Other currently active clinically significant Axis I psychiatric diagnosis including
schizophrenia, panic disorder, obsessive-compulsive disorder, generalized anxiety
disorder or post-traumatic stress disorder. Patients with severe Axis II personality
disorders will also be excluded if the personality disorder is likely to interfere
with cooperation and adherence to the study protocol.

- Current psychotic symptoms.

- Evidence of global cognitive impairment.

- Substance abuse or dependence not in full sustained remission (i.e., not active for at
least one year).

- Active suicidal ideation with intent; suicide attempt within the last six months; more
than three suicide attempts within the last two years.

- Pregnancy or plan to become pregnant during the study period.

- General contraindications for DBS surgery (cardiac pacemaker/defibrillator or other
implanted devices).

- Inability or unwillingness to comply with long-term follow-up.

- History of intolerance to neural stimulation of any area of the body.

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

- Conditions requiring repeated MRI scans.

- Conditions requiring diathermy.

- Conditions requiring anticoagulant medication.

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