The purpose of this study is to test the safety, efficacy and mechanism of action of subgenual cingulate (Cg25) deep brain stimulation (DBS) for major depression in patients who have not responded to prior antidepressant treatments. Participation in the study will continue for ten years or until the device receives FDA approval for depression. Forty (40) patients will be enrolled in this study.

Major Depression is one of the most common and costly of all psychiatric disorders. While depression can be effectively treated in the majority of patients by either medication or some form of evidence-based psychotherapy, up to 20% of patients fail to respond to standard interventions. For these patients, trial-and-error combinations of multiple medications and electroconvulsive therapy are often required. For patients who remain severely depressed despite these aggressive approaches, new strategies are needed.

Converging clinical, biochemical, neuroimaging, and post-mortem data suggest depression is unlikely to be a disease of a single brain region or neurotransmitter system. Rather, it is now generally viewed as a systems-level disorder affecting integrated pathways linking select cortical, subcortical and limbic sites and their related neurotransmitter and molecular mediators. Treatments for depression can be viewed within a limbic-cortical system framework, where different modes of treatment modulate specific regional targets, resulting in a variety of complementary, adaptive chemical and molecular changes that re-establish a normal mood state. Functional neuroimaging studies have played a critical role in characterizing these limbic-cortical pathways. Previous studies have demonstrated consistent involvement of the subgenual cingulate (Cg25) in both acute sadness and antidepressant treatment effects, suggesting a critical role for this region in modulating negative mood states.

This study will test whether high frequency deep brain stimulation of the subgenual cingulate white matter (Cg25-DBS) is a safe and efficacious antidepressant treatment in forty patients with treatment resistant depression, and to investigate potential mechanisms of action of this intervention.

Inclusion criteria:

• Ability to provide written informed consent.

• Current Major Depressive Episode (MDE), secondary to either Major Depressive Disorder or Bipolar Disorder (I, II or NOS), diagnosed by structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders-IV-text revision (DSM-IV-TR).

• Current MDE at least two years duration OR a history of more than 4 lifetime depressive episodes.

• Minimum score at study entry of 20 on the 17-item Hamilton Depression Rating Scale (HDRS-17).

• Average pre-operative HDRS-17 score of 20 or greater (averaged over four weekly pre-surgical evaluations during the four weeks prior to surgery) and an average pre-operative HDRS-17 score no more than 30% lower than the baseline screening HDRS-17 score.

• A maximum Global Assessment of Functioning of 50.

• Treatment-resistant depression defined as:

  • Failure to respond to a minimum of four different antidepressant treatments, including at least three medications from at least three different classes, evidence-based psychotherapy or electroconvulsive therapy (ECT) administered at adequate doses and duration during the current episode.
  • Failure or intolerance of an adequate course of electroconvulsive therapy (ECT) during any episode (confirmed by medical records), or refusal of ECT due to a reason considered to be valid by the study psychiatrist.

• A patient may remain on psychotropic medications during this study. However, doses must remain stable during the 4 weeks prior to surgery, the four weeks post-operatively, and the 24 weeks open stimulation phase. Medications will be changed only if intolerable side effects clearly attributable to the medications develop.

• All patients must have an established outpatient psychiatrist and be willing to sign a written release to allow study investigators to give and receive information from this psychiatrist.

Exclusion criteria:

• Inability to tolerate general anesthesia.
• 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.

28 participants underwent Subcallosal Cingulate Deep Brain Stimulation between January 2007 and June 2013.

Data for Adverse Events and Severe Adverse Events was collected during follow up time of the Primary Outcome (up to 24 weeks post intervention).