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 Research & Giving News Article  Targeted Deep Brain Stimulation Produced Early and Lasting Benefits in Group of 20 Chronically Depressed Patients In a study to be published in September in the journal Biological Psychiatry and made available this week online, Dr. Andres Lozano, neurosurgeon at Toronto Western Hospital, Dr. Helen Mayberg, professor of psychiatry and neurology at Emory University, and their colleagues in Toronto, report progress with an experimental mode of therapy called deep brain stimulation. DBS, as it is often referred to, is a form of electrical stimulation of nerve cells and fiber tracts in the brain. When applied in a highly specific brain area, the researchers report, it “produced robust improvements in depression” in a group of 20 patients who had not responded to antidepressant drug therapy, psychotherapy, or electroconvulsive therapy. “Benefits were seen over multiple domains of depression,” according to the research team, including improvements in mood, anxiety, and sleep disturbances associated with chronic major depression. These improvements tended to appear early and were sustained over time, up to the 12-month limit of the test, with a low relapse rate. “Overall, patients were markedly improved” after sustained treatment, the study indicates, which led “in certain cases to reintegration into their family and social activities and a return to their past work activities.” Continuous and Long-Lasting Effects The findings extend the preliminary results reported on six patients by Drs. Mayberg and Lozano in 2005, and include results of 14 additional patients. All of the experiments were conducted between 2003 and 2006 in Toronto. Dr. Mayberg is a three-time recipient of NARSAD grant awards: Young Investigator (1991), Independent Investigator (1995) and Distinguished Investigator (2002). She was honored with the organization’s Falcone Prize for Mood Disorders Research last year. Perhaps most important, Dr. Mayberg and colleagues found that when DBS was applied in a part of the brain called the subcallosal cingulate gyrus (SCG), a large percentage of patients with refractory depression responded positively, some within one month, and with some soon achieving what they describe as “remission” of depressed symptoms. The positive results were observed to be progressive, as the treatment helped more and more of the test subjects between one and six months of continuous DBS. They were also observed to be long-lasting, with no remissions one year after treatments began. “My colleagues and I have concluded that DBS, applied in the SCG, improves many of the symptoms of severe depression in patients who have failed to respond to conventional treatments,” Dr. Mayberg commented. “We noted improvements within one month that lasted for at least a full year. The procedure was well tolerated and none of our patients suffered a permanent serious adverse effect.” About the Patients and the Procedure The team of scientists, working out of facilities at Toronto Western Hospital, affiliated with the University Health Network and University of Toronto, applied DBS through a surgical procedure that while experimental for depression, is routinely performed for patients with severe Parkinson’s disease. Under local anesthetic, two holes were drilled in the skull. Using a sophisticated suite of imaging and electrical technologies, “pulse generators” -- electrodes that deliver a specific form of electrical stimulation -- were positioned with exquisite precision in the SCG, a part of the brain that prior research has linked to depression. All patients were released from the hospital within five days of surgery. The patients returned to the clinic at various intervals to enable the psychiatric and surgical teams to observe and adjust the implanted devices, which were designed to deliver stimulation continuously to this brain region over the extended period of the clinical trial. During the twelve months in which patients were studied, an attempt was made not to adjust medications they may already have been taking, so as not to throw into question any observed changes in the way they felt and behaved. The patients included nine men and 11 women, none of whom were suffering from other complicating conditions. All had failed multiple trials of drug therapy and psychotherapy, and all but three had also received a course of electroconvulsive therapy during the course of their current depressive episode, without positive result. The mean duration of the subjects’ current depressive episode was nearly seven years. The mean number of medications taken by the trial group was four. Patients were evaluated for depression before and during treatment using a standard measure, the 17-item Hamilton Rating Scale for Depression (HRSD-17), and were also tested for intellectual and cognitive function. 60 Percent Response in Six Months One exciting aspect of the results was the fact that “progressive improvement” in depressive symptoms was noted in these difficult-to-treat chronic patients. “From two weeks to six months after surgery, an increasing proportion of patients improved, reaching a plateau at six months,” the team wrote in their report. At the six-month point, fully 60 percent of patients were observed to be responding -- they were demonstrably helped by the treatment -- and 35 percent of the group achieved full remission of symptoms. Furthermore, “these benefits were largely maintained for the duration of the study,” the team wrote. Eight of 11 patients observed to be responding at six months were also responding after one year; three of nine patients who were not responding at six months showed a response by the one-year point. The responses to DBS treatment, where noted, were described by the team as “global,” with improvements seen in mood, level of anxiety, and sleep patterns. “Improvements in each of the symptom clusters increased with time after the initiation of stimulation,” they reported. The number of serious adverse effects was small, and no patients experienced permanent deficits. Four of the patients developed infections at the site of the surgery; this led to an improved procedure for implanting the pulse generator. Other impacts of the surgery included one seizure, and mood and headache problems in several patients. One patient experienced pain at the site of the implantation. Seven of the 20 patients suffered no adverse effects. The procedure, the researchers stressed, is fully reversible: the implants can be taken out (and were, in all cases) with no ill effects. The team observed no “cognitive adverse effects” in any of the 20 patients following the trial. How DBS Works in the Brain The research team hypothesizes that DBS disrupts pathological activity in brain circuits underlying depression and allows more normal cerebral function and behavior. But it is uncertain precisely how DBS brings about these postulated changes. “We do not know the precise mechanism of action at the cellular level,” they wrote in their report. It is known that the target of the electrical stimulation in DBS -- the subcallosal cingulate gyrus -- is connected via synapses, the tiny gaps between individual nerve cells, with structures in the brain’s cortex and subcortex that are involved in the pathology of major depression. Because of these “downstream” connections with the stimulated brain area, the team assumes that DBS is able to influence neuronal circuits directly involved in functions that are known to be perturbed in major depression: mood, cognition, sleep and circadian rhythms, appetite, regulation of cortisol, processing of pain, reward mechanisms and emotional reactivity. The team performed positron emission tomography (PET) scans of the brains of DBS test subjects that indicated “that DBS produces large changes in brain activity” in brain areas “downstream” from the region directly targeted, the SCG. “This suggests that . . . DBS [focused on the SCG] together with other therapies that also ameliorate depression exert their influences on a common set of neural substrates,” or targets, the team wrote. And this, in turn, suggests to the team that the positive improvements observed in test subjects were the results of actual changes in the activity of these “downstream” brain regions -- changes in metabolism the precise nature of which is not yet understood. The current set of results are extremely encouraging, the team stressed. They are an “initial step” that paves the way for a full “blinded” clinical trial, in which some subjects receive DBS treatment and some do not, but where no patient knows which group they are in. This eliminates the possibility of “subjective” evaluations creeping into evaluations of effectiveness. |
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