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Use of deep brain stimulation in treatment-resistant depression

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ABSTRACT

Deep brain stimulation has emerged as an experimental treatment option for the sizeable proportion of patients with major depression that is refractory to multiple medications and psychotherapy. Chronic stimulation of the ventral internal capsule/ventral striatum has been shown to improve function and mood in patients with severe obsessive-compulsive disorder, and has likewise been applied to patients with treatment-resistant depression. Multicenter experience with chronic deep brain stimulation of the ventral capsule/ventral striatum in 17 patients with severe treatment-resistant depression has demonstrated sustained improvements across multiple scales of depression, anxiety, and global function. Further research on deep brain stimulation in larger populations of patients with treatment-refractory depression is under way. While such research should benefit from the recent US Food and Drug Administration approval of deep brain stimulation for severe obsessive-compulsive disorder, it must adhere to strict principles for appropriate patient selection.


 

References

Deep brain stimulation (DBS) for severe, treatment-refractory depression has evolved out of both the troubled history of psychosurgery in the middle of the 20th century and the recent promising application of DBS for movement disorders and other neurologic and psychiatric conditions. This review describes the context in which DBS has emerged as an experimental therapy for refractory depression, explains the rationale for targeting stimulation to the ventral capsule/ventral striatum, and reviews promising results of preliminary clinical studies of DBS for depression.

PSYCHOSURGERY: A CLOUDED HISTORICAL BACKDROP

The use of DBS for depression is best understood within the context of the problematic history of neurosurgery for psychiatric conditions (psychosurgery), which dates back to the development of frontal leucotomy (ie, frontal lobotomy) by Egas Moniz and Pedro Lima in 1935. Walter Freeman, an American neurologist and psychiatrist without surgical training, performed the first prefrontal lobotomy in the United States in 1936. In 1945 Freeman pioneered the transorbital (“ice pick”) lobotomy, which accessed the frontal lobes through the eye sockets rather than by holes drilled in the skull. Freeman’s advocacy of lobotomy as an expedient therapy for psychiatric conditions helped fuel the procedure’s midcentury popularity, as more than 20,000 psychosurgery procedures were performed in the United States for various indications between 1936 and 1955.

Although some symptomatic improvement was seen with these psychosurgery procedures, they quickly became controversial because of their adverse effects, which included personality changes, as well as their perceived barbaric nature and their indiscriminate use by some practitioners. Moreover, little systematic research of these procedures was done, with most studies being poorly designed with little attention to long-term outcomes.

By the 1960s psychosurgery was in decline, largely because of the advent of effective psychopharmacology.

FROM BRAIN LESIONING TO BRAIN STIMULATION

Despite this decline, research on neurosurgery for the treatment of psychiatric conditions continued with small-scale studies of procedures involving smaller brain lesions, such as anterior capsulotomy and anterior cingulotomy using radiofrequency lesioning or gamma knife irradiation. Some of these studies demonstrated significant improvements, particularly in patients with severe obsessive-compulsive disorder (OCD).

These results prompted consideration of DBS for treatment of patients with severe psychiatric illness, especially since DBS offered several potential advantages relative to lesioning:

  • Reversibility
  • The ability to perform double-blind crossover studies
  • The ability to vary stimulation sites and parameters.

Briefly, DBS for psychiatric applications involves bilateral implantation of electrodes in the anterior limb of the ventral internal capsule extending into the ventral striatum. Each electrode has four individually programmable contacts. The neurostimulator is placed in a pocket created in the subclavicular area. The leads are connected to each neurostimulator by tunneling under the scalp and the skin of the neck to the pocket, permitting noninvasive adjustment of the electrical stimulation.

EXPERIENCE WITH STIMULATION IN OBSESSIVE-COMPULSIVE DISORDER

Greenberg et al reported outcomes of the use of DBS in 26 patients with severe and highly treatment-resistant OCD treated at four collaborating centers from 2000 to 2005.1 The target for stimulation was the ventral internal capsule/ventral striatum (VC/VS); this target evolved slightly over the course of the study as it became evident that outcomes were superior with targets that were more posterior. Concomitant pharmacotherapy was permitted throughout the study.

At 3 to 6 months after initiation of chronic DBS, scores on the Yale-Brown Obsessive Compulsive Scale, a measure of OCD severity, improved by an average of nearly 50% in these patients with severe refractory disease,1 which is notably better than the 35% improvement often used as the threshold for response in OCD trials. Improvement in mood was a beneficial side effect of DBS in the study, and in patients with comorbid depression, mood improved to a greater degree than did symptoms of anxiety and OCD.

In the wake of the initial release of this study by Greenberg et al (published online in May 2008) and similar findings, the US Food and Drug Administration (FDA) in February 2009 approved DBS for use in refractory OCD under a humanitarian device exemption. Such exemptions are granted to facilitate the development of devices for rare conditions, and the exemption was applicable in light of the rarity of severe, treatment-resistant, disabling OCD.

RATIONALE FOR BRAIN STIMULATION IN DEPRESSION

A large refractory and disabled population

In contrast to OCD, treatment-refractory depression is rather common, as approximately 20% of patients with depression—roughly 4.4 million US patients—have disease that is resistant to the mainstay treatment options of antidepressant medications and psychotherapy.2 The fact that electroconvulsive therapy is performed more than 100,000 times annually in the United States is another testament to how widespread treatment-resistant depression remains. Even if only some of these patients with severely disabling and refractory depression may be candidates for DBS, they represent a considerable potential patient population.

A pathophysiologic role for the VC/VS

The target for stimulation in OCD—the VC/VS—also has a known anatomic and physiologic role in depression, which makes it an appropriate surgical target for treatment of depression as well. Significantly less VS response to positive stimuli has been observed in depressed patients compared with controls.3 Moreover, the subgenual cingulate region is known to be metabolically hyperactive in patients with major depressive disorder, and positron emission tomography studies of OCD patients who underwent DBS of the VC/VS showed a reduction in subgenual cingulate activity over time.4

White matter tracts in the area 25 region adjacent to the subgenual cingulate cortex represent another target for stimulation. In a pilot study by Mayberg et al, DBS electrodes implanted bilaterally in the subgenual cingulate cortices of 6 patients with treatment-resistant depression resulted in sustained remission of depression in 4 patients at 6 months.5 The benefit of stimulation continued for up to 4 weeks after stimulation ended.

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