Deep Brain Stimulation (DBS) for Depression Using Directional Current Steering and Individualized Network Targeting

Treatment-resistant depression (TRD) is a major worldwide burden. Major depression has a
lifetime prevalence of ~15% across developed countries. Up to a third of patients fail to
respond adequately to evidence-based treatments, including pharmacological, behavioral, and
electroconvulsive therapy. The investigators employ an innovative approach, including
subacute invasive neurophysiological monitoring with which they aim to gain insight into the
networks underlying depression symptomatology, confirm the ability to predict the effects of
precision DBS on network activity, and harmonize these insights to implement network-guided
DBS for TRD.

Inclusion Criteria:

- Men and women (non-pregnant) between ages 21 and 70;

- Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) diagnosis (assessed by
Structured Clinical Interview for DSM-5 Axis I disorders (SCID2)) of a current major
depressive episode (MDE), recurrent or single episode with first episode before age
45, secondary to nonpsychotic unipolar major depressive disorder;

- Chronic illness with current MDE ≥24 months duration and/or recurrent illness with at
least a total of 2 lifetime episodes (including current episode >12 months);

- Treatment resistance (defined by criteria on the Antidepressant Treatment History Form
(ATHF)3): Failure (i.e. persistence of the major depressive episode) to respond to a
minimum of four adequate depression treatments from at least two different treatment
categories (e.g. SSRI's, serotonin-norepinephrein repute inhibitors (SNRIs), TCA's,
other antidepressants, lithium-addition, irreversible monoamine oxidase inhibitor
(MAOI), antidepressant augmentation with an atypical antipsychotic medication), and
repetitive transcranial magnetic stimulation (rTMS);

- Previous trial of Electroconvulsive Therapy4 (ECT) (lifetime): either did not respond,
relapsed, poorly tolerated or refused. If refused, will discuss reasons and ensure
subject understands relative risks of ECT versus DBS.

- We will try to enrich sample with patients who had previously shown response to ECT
(or another intervention) that was partial or un-sustained;

- A prior trial of ketamine will not be required because it is not FDA approved and
durable responses have not been demonstrated,5 nevertheless, subjects will be informed
about this possible off-label option;

- Symptom severity for Screening: Hamilton Depression Rating Scale-17 item (HDRS176)
≥20;

- The HDRS17 must remain greater than or equal to 20 on two separate assessments (at
initial screening and 1 week before surgery), over a 1-month period;

- Symptom severity for Outcome: Montgomery Asberg Rating Scale (MADRS7) ≥27 to be met at
assessment one week pre-op;

- Normal brain MRI within 3 months of surgery;

- Stable antidepressant medication regimen for the month preceding surgery;

- Modified mini-mental state examination (MMSE8) score ≥ 24;

- Normal thyroid stimulating hormone (TSH) level within 12 months of study entry;

- Other medical conditions must be stable for at least 6 months;

- Able and willing to give informed consent and agree to attend regular clinic visits
for at least 12 months following surgery.

- Willingness to sign Treatment Contract

Exclusion Criteria:

- DSM-5 Axis I Disorders: any lifetime history of psychotic disorder (e.g.
schizophrenia, schizoaffective disorder); or other serious disorders: bipolar
disorder, obsessive-compulsive disorder (OCD), PTSD, anorexia nervosa, in the last
year;

- Clinically significant Cluster A or B personality disorder;

- Alcohol or substance use disorder within 6 months, excluding nicotine;

- Current substantial suicidal risk as defined by a plan or clear immediate intent for
self-harm, or made a suicide attempt within the last year;

- Neurological/Medical condition that makes the patient, in the opinion of the surgeon,
a poor candidate.

- Any history of seizure disorder or hemorrhagic stroke;

- Any medical contraindication to surgery, including infection or coagulopathy;

- Participation in another drug, device, or biological trial within 30 days;

- Current implanted stimulation devices including cardiac pacemakers, defibrillators,
and neurostimulators including spinal cord stimulators and deep brain stimulators;

- Pregnant or has plans to become pregnant in the next 24 months.

- Anticipated need for MRI for current medical condition.

- Need for Diathermy