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

Study Overview
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Brief Summary
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This study will evaluate the safety and effectiveness of deep brain stimulation in treating people with severe and otherwise treatment-resistant obsessive-compulsive disorder.

Detailed Description
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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.

Official Title
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Controlled Trial of Deep Brain Stimulation for Obsessive-Compulsive Disorder

Conditions
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Obsessive-Compulsive Disorder

Intervention / Treatment
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* Device: Active DBS
* Device: Sham DBS


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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active DBS<br>Participants will receive deep brain stimulation. | Device: Active DBS<br>* In DBS, thin wires are used to carry electric current to the parts of the brain involved in OCD symptoms. These wires are implanted surgically and are attached to battery operated stimulators usually implanted in the chest. The study doctor will adjust the settings of the electrical stimulation to optimize treatment for each participant. After a post-operative rest, participants will receive immediate DBS treatment throughout.<br>* Other names: Implantable Neurostimulator (INS);|
| Sham Comparator: Sham DBS<br>Participants will receive sham deep brain stimulation for several months and then active deep brain stimulation thereafter. | Device: Active DBS<br>* In DBS, thin wires are used to carry electric current to the parts of the brain involved in OCD symptoms. These wires are implanted surgically and are attached to battery operated stimulators usually implanted in the chest. The study doctor will adjust the settings of the electrical stimulation to optimize treatment for each participant. After a post-operative rest, participants will receive immediate DBS treatment throughout.<br>* Other names: Implantable Neurostimulator (INS);Device: Sham DBS<br>* In DBS, thin wires are used to carry electric current to the parts of the brain involved in OCD symptoms. These wires are implanted surgically and are attached to battery operated stimulators usually implanted in the chest. The study doctor will mimic adjusting the settings of the electrical stimulation. After a post-operative rest, participants will receive DBS treatment after a delay of several months. Afterwards, all participants will receive open-label long-term DBS.<br>* Other names: Implantable Neurostimulator (INS);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Yale-Brown Obsessive-Compulsive Scale (YBOCS Severity Ratings) | The Yale-Brown Obsessive-Compulsive Scale (YBOCS) is a 10 question evaluator-administered measure assessing the severity of obsessions and compulsions over the past week. Obsession and compulsion severity are evaluated separately (ratings from 0-20 for each category) with total scores ranging from 0-40. Higher scores for obsessions, compulsions and total score indicate more severe symptoms over the past week. | YBOCS total score observed means at month-12 | 
| Global Assessment of Functioning Scale (GAF) | A numeric scale (0 through 100) used to rate the social, occupational, and psychological overall functioning during the week of poorest functioning in the past month. Higher scores indicate a higher level of functioning, while low scores indicate impaired global functioning. | GAF score observed means at month-12 | 
| Social and Occupational Functioning Assessment Scale (SOFAS) | A numeric scale (0 through 100) used to rate the social, occupational, and psychological functioning during the week of poorest functioning in the past month. Higher scores indicate higher levels of social and occupational functioning, while low scores represent social and occupational impairment. | SOFAS score observed means at month-12 time point. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ) | The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) is a self-administered measure to assess the degree of enjoyment and satisfaction experienced by participants in various areas of daily functioning. We used the 16-item short form with total scores ranging from 16-80. Higher scores indicate greater satisfaction experienced during the past week. | QLESQ total score observed means at month-12 time point. | 
| Montgomery-Asberg Depression Rating Scale (MADRS) | The Montgomery Asberg Depression Rating Scale (MADRS) is an interviewer-administered measure assessing the ten symptoms of depression most sensitive to change. Apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts are assessed and total scores range from 0-60 with higher scores representing the presence of more severe depression over the past week. interviewer-administered measure assessing | MADRS total score observed means at month-12 time point. | 
| Hamilton Anxiety Rating Scale (HARS) | Hamilton Anxiety Rating Scale (HARS) is a 14-item test measuring the severity of anxiety symptoms. It provides measures of overall anxiety, psychic anxiety (mental agitation and psychological distress), and somatic anxiety (physical complaints related to anxiety); total scores range from 0-56. Higher scores indicate higher levels of anxiety over the past week. | HARS total score observed means at month-12 time point. | 
| Behavioral Activation for Depression Scale (BADS) | The Behavioral Activation for Depression Scale (BADS) is a 29-item scale that measures the role of aversive controlling stimuli and escape and avoidance behavior in depression, specifically when and how participants become more activated over the course of treatment. Total scores range from 29-203 and lower scores indicate higher levels of escape and avoidance behavior from depression in the past week. | Total BADS score observed means at month-12 time point. | 
| Hamilton Depression Rating Scale (HDRS) | The Hamilton Depression Rating Scale (HDRS) measures the severity of depressive symptoms in adults. The evaluator-administered ratings measure depressed mood, guilt, suicide, insomnia, work/activities, retardation, agitation, psychic and somatic anxiety, genital symptoms, hypochondriasis, and insight during the past week. Total scores range from 0-72 and higher scores indicate the presence of more severe depression over the past week. Note: this measure was only administered at baseline and month-3. | Total HDRS score observed means at month-3 time point. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Deep Brain Stimulation, Treatment Refractory, Ventral Internal Capsule/Ventral Striatum, Neurosurgery, Neuroimaging