Brain Stimulation for OCD: Delicate Balancing Act Needed

Deep brain stimulation may be an effective treatment for patients with severe, treatment-resistant obsessive compulsive disorder, but the surgery and procedure carry risks, a French study reported in the November 13 New England Journal of Medicine shows.

In the randomized, double-blind, sham-controlled, crossover study, 16 patients with moderate to severe obsessive-compulsive disorder (OCD) who had not responded to multiple drug therapies underwent brain surgery to have a deep brain stimulation (DBS) device implanted in the subthalamic nucleus region.

Eight patients were randomized to active stimulation for three months, followed by one month of wash-out, and then crossed over to sham stimulation for another three months. The other eight patients received sham stimulation first, followed by wash-out and active stimulation.

The mean Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores, a 40-point standard instrument used to measure the severity of OCD symptoms, were 30 at baseline, 28 after three months of sham stimulation, and 19 after three months of active stimulation. The active stimulation was significantly superior to sham stimulation in reducing the symptoms.

A Y-BOCS score of 16 to 23 corresponds to moderate symptoms, 24 to 30 to severe symptoms, and 31 to 40 to extreme symptoms. The study patients had suffered from OCD for an average of 18 years and had failed adequate treatment courses of at least three serotonin-reuptake inhibitors, one of which was clomipramine, with augmentation with another psychoactive drug.

Other indicators for treatment effectiveness, such as level of functioning and clinician-assessed overall disease severity, were both significantly more improved after active stimulation than with sham stimulation.

This study was supported by grants from the Programme Hospitalier de la Recherche Clinique Assistance Publique–Hôpitaux de Paris and the Agence Nationale de la Recherche Program for Young Researchers.

Adverse Events Sometimes Serious

A total of 15 serious adverse events occurred in the trial, of which four were deemed to be related to the surgery. In one patient, brain hemorrhage resulted in permanent finger palsy. Two patients had serious infections that led to the removal of the device. Seven cases of motor and psychiatric symptoms, including transient hypomania, were induced by the stimulation in the first month, but resolved spontaneously or after adjusting the device setting.

The DBS surgery and long-term stimulation “may reduce the symptoms of severe OCD but is associated with a substantial risk of serious adverse events,” the authors, led by Luc Mallet, M.D., Ph.D., of the Clinical Investigation Center at the French National Institute of Health and Medical Research, concluded.

“To the authors' credit, they emphasized the risks of serious adverse events,” Benjamin Greenberg, M.D., Ph.D., a psychiatrist in the Division of Neurosurgery at Butler Hospital and a professor of psychiatry and human behavior at Brown Medical School, told Psychiatric News. “The surgical side effects in this study were not very different from those of ablative surgeries such as anterior capsulotomy and anterior cingulotomy performed at very experienced U.S. centers.”

For patients with severe, refractory OCD who have exhausted noninvasive options, ablative surgery, in which neurons in targeted brain regions are destroyed, has been used as a last-resort treatment. The locations of DBS in current research are generally based on the same targeted regions.

Greenberg and colleagues published results from their long-term, international, collaborative trials of DBS for the treatment of refractory OCD in Molecular Psychiatry online on May 20. Twenty-six patients with severe, refractory OCD received DBS for at least a year; about half of them were followed for three years. Unlike the French study, these researchers targeted the ventral internal capsule/ventral striatum region of the brain. About two-thirds of patients gained “clinical significant symptom reductions and functional improvement,” the report concluded.

“DBS and surgical lesions do not work upon a particular spot in the brain but rather through circuits,” Greenberg explained. Although ablative surgeries and DBS studies have been applied to several different locations in the brain, they affect overlapping circuitries or some of the same nerve fibers, thus resulting in similar therapeutic effects on OCD symptoms.

Clinical Use Not Expected Soon

Despite the hopeful efficacy data, DBS is still a long way from clinical use for OCD. “It will be very important to know how the overall adverse events and effectiveness of DBS compare with [ablative surgery],” Greenberg emphasized. Although DBS is reversible, and ablative surgery is not, DBS requires intensive postsurgery adjustments of the device setting and long-term follow-up by a team of experienced neurologic, psychiatric, and other medical specialists, which may place more burden on some patients.

Researchers are exploring the effects of varying wire placement, stimulation parameters, patient characteristics, and other factors on outcomes in order to maximize benefits and minimize side effects and select patients most likely to respond to DBS. Greenberg is one of the principal investigators for a randomized, double-blind, sham-controlled, multisite DBS trial in treatment-resistant OCD. The study is sponsored by the National Institute of Mental Health and is currently recruiting patients.

An abstract of “Subthalamic Nucleus Stimulation in Severe Obsessive–Compulsive Disorder” is posted at<content.nejm.org/cgi/content/short/359/20/2121>. An abstract of “Deep Brain Stimulation of the Ventral Internal Capsule/Ventral Striatum for Obsessive-Compulsive Disorder: Worldwide Experience” is posted at<www.nature.com/mp/journal/vaop/ncurrent/abs/mp200855a.html>.▪