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Stimulation Device Offers Relief from Hard-to-Treat Depression

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Although great strides have been made in treating depression, those who suffer from treatment-resistant depression have continued to present a serious challenge to doctors seeking a way to help them.

Researchers at Medical University of South Carolina in Charleston recently broke new ground by using a revolutionary technique that holds promise for the severely depressed: bilateral epidural prefrontal cortical stimulation, a neurosurgical treatment.

The procedure is a form of brain surgery. It consists of implanting four paddles that deliver chronic and intermittent electrical stimulation to the surface of the part of the brain governing mood and socialization. The device that's inserted is similar to a pacemaker and has already been used to stimulate the spine as a means of combating pain.

"We're focusing on a very small but fairly disabled group of depressed patients," explained Dr. Ziad Nahas, who spearheaded the study and recently published the results in the journal Biological Psychiatry. Dr. Nahas has been studying brain stimulation and the pathophysiology of depression using brain imaging for over a decade. He has close to one hundred scientific publications and is the director of the Mood Disorders Program at the university. "These patients have typically failed many treatments and have suffered recurrent and severe depression for decades. Because of the experimental nature of our approach, they had to meet many criteria [to be part of the study] -- primarily, that there didn't seem to be another option for them.

"For an antidepressant treatment to work, it should not only improve depressive symptoms but also allow the patients to disengage from their attention to negative emotions and appraise their world with a wider range of experiences," Nahas continued. "I hypothesized five years ago that if we could deliver direct and chronic stimulation over areas of the brain that are involved in regulating mood and social behavior, we might be able to treat depression and sustain the improvement much longer than we typically see with current available therapies.

"Conceptually, we know that the anterior and lateral regions of the front of the brain have different roles but ultimately complement each other to ensure the person's well-being. They also are connected to deeper brain structures and thus are a part of larger networks. I asked, If these complementary networks are there, why restrict ourselves to stimulating one and not both?

"The lateral part of brain keeps track of the outside world and regulates information and the emotional responses," Dr. Nahas added. "The most anterior and the middle areas are more involved in our social interactions and how we define ourselves. Both play a critical role in how we ultimately feel. That was the innovative part of our approach. We were theoretically targeting these specific regions and saying, Let's try to change the activity in these two complementary networks. And by focusing on the surface of the brain as a ‘port of entry' to our therapy, we don't risk damaging any brain tissue."

Identifying Candidates for Neurosurgical Treatment

Dr. Nahas's study, which received funding from NARSAD, focused on five patients whose progress was followed for seven months. Candidates were adults between the ages of 31 and 57 who were fairly healthy medically. Patients with both unipolar and bipolar depression were included.
First and foremost, they had to show evidence of treatment resistant depression, defined as having failed at least four full-blown anti-depressant treatments, such as drug therapy, ECT and transcranial magnetic stimulation, in the current depressive episode. They all failed talk therapy.

"If someone tried Prozac for one week, it doesn't count," Dr. Nahas said. "But if the patient took nortriptyline for eight weeks, with a documentation of therapeutic blood level, and it still didn't work, that counts as a failure."

All five were unemployed, and three were on disability. Two were physicians who were no longer able to work. They all resided in the Charleston, South Carolina area, where the study was conducted. Candidates for the study also had to have an independent psychiatrist who agreed that all other options had been exhausted, as well as a patient advocate to represent the patient's best interests.

A Revolutionary Procedure

The procedure, first done in February 2008, consists of implanting paddles directly over the anterior poles and the lateral parts of the frontal cortex, two on the left hemisphere and two on the right, while the patient is under light sedation.

For the study, the devices were donated by their manufacturer, Minneapolis-based Medtronic, Inc. The patient is put under general anesthesia, and batteries are connected to the paddles and implanted in the anterior chest wall area.

The doctors who performed the surgery were able to see the results immediately in some patients - even before leaving the operating room.

"Once we placed all four paddles, the wires were connected to an external stimulator," Dr. Nahas explained. "We lifted sedation completely and waited ten minutes until the patient was fully alert. By that time, they were obviously very tired, having been in the OR for three hours. Their mood was low.

"We put a laptop in front of them," he continued. "Prior to surgery, they had used a scale of 1 to 100 to rate such statements as 'I feel settled emotionally,' 'I feel trustful,' and 'I feel sad.' We had them rate the statements once again by moving the cursor, giving their subjective impression in the moment. Without them knowing, we ran through a series of tests in which we either had no stimulation or we stimulated the paddles at different intensities."

The effects of the stimulation were sometimes dramatic. "As a group, we had a significant effect on their mood in the moment," Dr. Nahas said. "Anxiety was reduced and a couple of patients noticed feeling much more alert. Immediately one of the patients said, 'Have you done something?' When we asked why, she said, ' I feel like something is lifting off my shoulders.' Another experienced a feeling of clarity and could tell things were brighter."

Dr. Nahas added, "We can't say there isn't a placebo effect, the result of anticipation and wanting to get better, but some of the time we tricked them by saying, 'What do you feel now?' when in fact we had their devices completely turned off. We compared notes on responses when there was no active stimulation and saw no distinct changes in mood, anxiety or attention."

The researchers were concerned not only about the immediate effects of the treatment, but also about sustaining the response. Their goal was to train the brain in order to feel good. The main goal of the study was to look for clinically significant improvement in their depression after several months of treatment.
"Even if they get well acutely, there's such a tendency to rapidly relapse because the brain reverts back to the depression state," Dr. Nahas said. "Implanting a pacemaker that regularly and repeatedly stimulates over days and weeks and months may helps avoid that."

Evaluating the Results

The real measure of the technique's effectiveness was its effects over time. The researchers compared each patient's average depression score when he or she first came in with the average depression score at seven months after the procedure had been performed. Once again, the results were encouraging, with three of the five patients symptom-free by seven months.

"Over time, the group gradually started getting better," Dr. Nahas reported. "By seven months, we had three patients reach remission, meaning they were completely symptom free. On average, the group was 55 percent improved if you considered an objective measure, the Hamilton Rating Scale for Depression. With subjective measures, the rate of improvement was 60 percent.

"Not all five are remarkably better," he added. "One patient did not show much improvement. And one has improved 40 percent but plateaued and is still struggling with depression. But the quality of life for the patients who responded is amazingly different." One of the physicians who was formerly disabled, he noted, is now volunteering in a medical clinic.

"What's very important to emphasize is that we are early in the game," Dr. Nahas cautioned. "But we've shown that the procedure is safe and can potentially help TRD patients. Now we need to work on more definitive studies."

Editor's Note: Dr. Mark S. George also participated in this
study.

The Study's Authors: Ziad Nahas (1,2), Berry Anderson (1), Jeff Borckardt (1,3), Ashley B. Arana (1), Mark S. George (1,2,5,6), Scott T. Reeves (3), Istvan Takacs (2,4).
1 - Department of Psychiatry, Mood Disorders Program and Brain Stimulation Laboratory
2 - Department of Neuroscience
3 - Department of Anesthesia and
Perioperative Medicine
4 - Department of Neurosurgery
5 - Department of Radiology, Medical University of South Carolina, Charleston, SC; USA
6 - Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA

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We value and respect our HERWriters' experiences, but everyone is different. Many of our writers are speaking from personal experience, and what's worked for them may not work for you. Their articles are not a substitute for medical advice, although we hope you can gain knowledge from their insight.

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