Effectiveness of Deep Brain Stimulation for Treating People With Treatment Resistant Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a chronic and debilitating illness that affects
between 2% and 3% of adults in the United States. People with OCD often experience persistent
unwanted thoughts and carry out ritual-like behaviors to rid themselves of these obsessive
thoughts. Additionally, OCD symptoms are usually tied with feelings of intense anxiety and
functional impairment, making it important for people with OCD to seek effective treatment.
Although there are currently many treatment options for OCD, including psychotherapy and
medications such as serotonin reuptake inhibitors, between 40% and 60% of people with OCD
only partially respond or do not respond at all to these treatment methods. Given the large
percentage of people who do not respond to aggressive conventional treatments, alternative
options are necessary for people with treatment-resistant OCD. Deep brain stimulation (DBS)
is a procedure that involves the use of thin wires to carry electric current to parts of the
brain associated with producing OCD symptoms. DBS has been effectively and safely used to
treat movement disorders, such as Parkinson's disease, and may be beneficial in reducing OCD
symptom severity. This study will evaluate the safety and effectiveness of DBS in treating
people with severe and otherwise treatment-resistant OCD.

Study participation through follow-up will last 4 years. Participants will be allowed to
remain on any pre-surgical medications or behavioral therapy programs throughout the study.
Before surgery, all participants will undergo a 3- to 4-day series of initial tests and
examinations that will include a physical and neurological examination; blood and urine
screening tests; an electrocardiogram (EKG); an electroencephalography (EEG); and detailed
psychological testing, including tests of perception, learning, and memory. The EEGs may be
performed again after surgery to measure potential changes in brain electrical activity due
to DBS.

On the day of the surgery, participants will take a low dose of anxiety medication, have a
metal frame fixed to their heads for support during surgery, and undergo a magnetic resonance
imaging (MRI) scan to determine where to place the stimulating wires. After being injected
with a local anesthetic, participants will undergo the first part of the operation, which
will involve the implantation of neurostimulators in the ventral caudate/ventral striatum
brain region. For the second part of the operation, after participants are administered
general anesthesia, they will have the implantable neurostimulators (INSs) placed in their
chests and the connecting wires to the brain placed under their skin. The entire surgical
procedure will take 3 to 4 hours, with a 1- to 2-day post-operative hospital stay for
recovery. During the post-operative stay, participants will undergo x-rays and a computed
tomography (CT) scan of the head.

Two to 3 weeks after surgery, participants will be divided randomly into either a group that
receives DBS immediately or a group that first receives sham DBS and then active DBS after 3
months. The level of stimulation will be adjusted individually and on the basis of each
participant's response to the stimulation. Participants will complete rating forms, a
clinical evaluation, and a check of the stimulators every month for the first 3 months, then
at least every 3 months for the rest of the year, and then every 6 months for the remaining
years of the study. On the Year 1 visit, participants will repeat the baseline detailed
psychological testing. Periodically throughout the 4-year study, staff will contact
participants by phone to ask about OCD symptoms, mood, anxiety, and possible side effects.
Also throughout the study, participants will need to have the INSs replaced every 5 to 16
months on average.

Participants will also be invited to participate in a related study that involves positron
emission tomography (PET) scanning to determine how the stimulation changes activity in the
brain. Participation in the separate PET study is optional and will not affect current study
participation.

Inclusion Criteria:

- Obsessive-compulsive disorder (OCD), diagnosed by Structured Clinical Interview for
DSM-IV (SCID-IV)

- Presence of disabling severity, as assessed by a Yale-Brown Obsessive Compulsive Scale
(YBOCS) score of at least 30

- Impaired functioning, indicated by a Global Assessment of Functioning (GAF) score of
45 or less

- Documented highly treatment refractory illness; the documentation must demonstrate
persistence of severe symptoms and impairment for 5 or more years despite at least
three first-line and two second-line treatments, as follows:

1. at least three adequate trials of, or documented intolerance to, different
serotonin transporter inhibitors (e.g., fluoxetine, sertraline, fluvoxamine,
paroxetine, citalopram, escitalopram, clomipramine) for at least 3 months at the
maximum tolerated dose. These trials may include any of the agents above, but
must include an adequate course of clomipramine, either alone or in combination
with a more selective serotonin transporter inhibitor;

2. augmentation of one of the selective serotonin transporter inhibitors with
clomipramine, and a neuroleptic (each for at least 2 weeks); and

3. adequate behavior therapy (more than 20 sessions of exposure and response
prevention by a therapist with substantial expertise in OCD treatment as
determined by the investigators) with at least one of these trials and tried in
combination with medication therapy

- Either drug free or on a stable drug regimen for at least 6 weeks before study entry

- General good overall health

- If possible, has a family member or significant other who sees the participant
regularly, can communicate with the study team as needed, and, if necessary, can
attend study visits

- Local referring psychiatrist willing to provide ongoing care during and after the
trial, to work closely with the research team, and to agree that the study
psychiatrist will prescribe medications during the 3-month masked phase

- Platelet count greater than 125,000 per cubic millimeter and a prothrombin time and
partial thromboplastin time within normal limits

Exclusion Criteria:

- Current or past psychotic disorder

- Full-scale IQ below 75 on the Wechsler Abbreviated Scale of Intelligence (WASI), or
cognitive impairment that would affect a participant's ability to give informed
consent or provide interview or self-report data reliably, as determined by the
Consent Monitor and the site psychiatrist.

- A clinical history of bipolar mood disorder

- Any current clinically significant neurological disorder or medical illness affecting
brain function, other than a tic disorder

- Any clinically significant abnormality on preoperative MRI

- Any labeled DBS contraindication, inability to undergo presurgical MRI (e.g., cardiac
pacemaker, pregnancy, metal in body, severe claustrophobia), infection, coagulopathy,
inability to undergo an awake operation, significant cardiac risk factors, or other
medical risk factors for surgery

- Current or unstable remitted substance abuse or dependence

- Positive urine toxicology screen for substance abuse

- Pregnant and/or woman of childbearing age not using effective forms of birth control

- Clinical history of severe personality disorder

- An inability to control suicide attempts, imminent risk of suicide in the
investigator's judgment, or a history of serious suicidal behavior, which is defined
using the Columbia-Suicide Severity Rating Scale (C-SSRS) as either (1) one or more
actual suicide attempts in the 3 years before study entry with the lethality rated at
3 or higher, or (2) one or more interrupted suicide attempts with a potential
lethality judged to result in serious injury or death

- Current diagnosis of body dysmorphic disorder

- Evidence of dementia of other significant cognitive impairment on neuropsychological
evaluation