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Evidence continues to mount that deep brain stimulation (DBS) may send a ray of light into the bleak world of people suffering from severe, intractable depression.

Fifteen percent to 30 percent of depressed patients are unresponsive to drugs, psychotherapy, electroconvulsive therapy, or any combination of the three. In an effort to help these refractory patients, investigators are studying techniques that affect neural function directly. The Food and Drug Administration (FDA) approved vagus nerve stimulation as a treatment for intractable depression last July. Other candidates include transcranial magnetic stimulation and magnetic seizure therapy, as well as DBS, but it's DBS that currently seems to hold the most promise, experts say.

At the annual meeting of the American Association of Neurological Surgeons in April, Ali Rezai, MD, Director of Functional Neurosurgery at the Cleveland Clinic, presented preliminary findings on nine patients who had DBS in the ventral capsule/ventral striatum region for depression between 2003 and 2005. The study developed from observations in patients with intractable obsessive-compulsive disorder (OCD), about two-thirds of whom also have depression, Dr. Rezai explained. In an earlier study of patients with treatment-resistant OCD and comorbid depression who received DBS in the same area, “we noted that in addition to improvement in OCD scales, depression scores also improved significantly.”


Dr. Ali Rezai: “We could not do a blinded phase, because every time we turned the DBS off, the patients became depressed.”.


In this study, a joint venture between the Cleveland Clinic and Brown University, the patients had DBS electrodes implanted bilaterally in the ventral internal capsule/ventral striatum region located in front of the anterior commissure. This area encompasses the caudal portion of the nucleus accumbens and the rostral part of the red nucleus, Dr. Rezai explained. The area is rich in serotonin and contains longitudinal white matter fibers that link the orbitofrontal cortex, mesiofrontal cortex, and dorsolateral frontal cortex to the thalamus, hypothalamus, amygdala, and brainstem.

“Only the most severe, disabled, and highly treatment-resistant patients” were recruited, Dr. Rezai said. The patients experience persistent depression for at least five years and they had had multiple courses of treatment with drugs, psychotherapy, and electroconvulsive therapy. After surgery, the patients continued their usual regimen of medication and psychotherapy.

The effects were immediate and complex, including marked improvement in mood, alertness, spontaneity, verbal fluency, vital signs, and decreased anxiety. In fact, “we could not do a blinded phase, because every time we turned the DBS off, the patients became depressed,” Dr. Rezai recalled.


The overall result was a balancing of mood: patients still felt sad on occasion, but now they could also feel happy. The big difference was that the feelings were appropriate to the circumstances, and the sadness was transient and not immobilizing, as it had been before.

An evaluator blinded to the electrical settings assessed each patient. At the one-year follow-up assessment, two-thirds of the patients met the response criterion of at least a 50 percent reduction in severity of depression, as measured by the Montgomery-Asberg Depression Rating Scale.

They also showed significant improvement over baseline in Hamilton Depression Rating scores and in global assessment of functioning, effects that persisted at the 18-month assessment. Suicidal feelings subsided rapidly, and the patients ultimately returned to work, family activities, and hobbies. Neuropsychological tests demonstrated improvement in short-term memory, with no decline in function.


These results support data published last year by Helen Mayberg, MD, Andres Lozano, MD, PhD, and colleagues at Toronto Western Hospital. They saw marked improvement in four of six severely depressed patients who underwent DBS (Neuron 2005;45:651-660).

However, the Toronto investigators focused on a different part of the brain. They performed PET imaging on depressed patients and saw activation in cingulate area 25 when the patients felt sad. The activity subsided when the patients reported lifting of the depression in response to medication. Based on those studies, Drs. Mayberg and Lozano made area 25 the target of the DBS electrodes.

The areas targeted by the two teams are not contiguous. “They're more like interconnected highways that use different routes to reach some of the same and some different destinations,” said Dr. Lozano, who was not involved in the Cleveland Clinic study.


Dr. Rezai and his colleagues “employed what I consider to be all of the appropriate pre-surgical selection criteria, and have used clinically validated rating scales and all of the appropriate institutional safeguards,” G. Rees Cosgrove, MD, Professor of Neurosurgery at Tufts School of Medicine and Chairman of Neurosurgery at Lahey Clinic Medical Center, said in an independent comment following Dr. Rezai's presentation.

The response criterion of a greater than 50 percent improvement in depression rating scales is the same criterion used in studies of novel pharmacological treatments of depression, added Dr. Cosgrove.

The two-thirds response rate they obtained is virtually identical to the results achieved with cingulotomy, subcaudate tractotomy, and limbic system surgery, he noted.

However, DBS should be viewed as an adjunct to other forms of therapy, rather than a cure, Dr. Cosgrove warned. Several important questions remain, including:

  • What is the exact mechanism of action?
  • What are the most appropriate target sites?
  • What should be the patient selection criteria?
  • Who is going to pay for the procedure?
  • What happens when the batteries expire? It could be a psychiatric emergency if patients abruptly sink back to their previous level of depression.

DBS is reversible, making it an attractive last-resort option for severely depressed patients, Ghassan Bejjani, MD, Clinical Associate Professor of Neurosurgery at the University of Pittsburgh Medical Center, told Neurology Today in an interview. He was not involved in the study.

But he agreed that expense is indeed a drawback: the device alone costs about $15,000. And the risks that accompany any type of surgery cannot be dismissed.

DBS will probably never become a first-line treatment, but “for patients who have no other option, this definitely has potential,” he said.


  • ✓ In a small preliminary trial, investigators reported that there were marked improvements in mood, alertness, spontaneity, and verbal fluency in patients with refractory depression who had undergone deep brain stimulation.


• Mayberg HS, Lozano AM, Kennedy SH, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45:651-660.