Deep brain stimulation lifts severe depression; Technique may suppress activation of brain region that malfunctions in cases of resistant disease.

BARCELONA -- Deep brain stimulation of the subcallosal cingulate gyrus significantly improved the symptoms of treatment-resistant depression, both by suppressing activation of that area and remotely activating other brain regions involved in pathogenesis of the illness, study results have shown.

Within 6 months of the surgery, 12 of 20 patients had a significant decrease in depressive symptoms (a decrease in the Hamilton Rating Scale for Depression of at least 50%), and 7 of those were in remission, with a Hamilton score of less than 8, Dr. Andres M. Lozano said at the annual congress of the European College of Neuropsychopharmacology.

"I think we have shown that there is a brain circuit that malfunctions in cases of severe depression, and that deep brain stimulation [DBS] can modulate the activity of this circuit," he said.

Dr. Lozano, who is professor and R.R. Tasker Chair in Functional Neurosurgery at the University of Toronto, said the subcallosal cingulate gyrus (SCG) was a perfect target for neuromodulation because of its role in mood regulation and its intricate neural connections with other brain regions involved in depression.

In normal subjects, the SCG shows activation in response to sad images, while in depressed patients, antidepressant medications reduce its activation, he said. The region also is directly connected to the hypothalamus and its regulation of sleep and appetite; the amygdala, with its effect on stress response and circadian rhythm; and the shell of the nucleus accumbens, which is involved in reward, motivation, and perhaps even the anhedonia often present in depression. "So changes in the SCG may result in widespread changes in areas throughout the brain," Dr. Lozano said.

He reported the results of a 20-patient series--the largest to date. Published in July, the study expands on a 2005 report of six patients who received the implants. The new report examines results for the original 6, plus 14 more patients, all of whom have had the stimulators for at least 12 months (Biol. Psych. 2008 July [doi:10,1016/jbiopsych.2008.05.034]).

The patients' mean age was 47 years. All had a long history of treatment-resistant major depression; the mean length of the current episode was 7 years. Patients had to have failed treatments in at least four different categories, and failed or refused electroconvulsive therapy. At baseline, the mean Hamilton depression score was 24.

Many patients reported changes in perception as soon as the stimulators were activated in the operating room, Dr. Lozano said. These changes occurred within seconds of turning on the current. The patients "reported an intense sense of calm, quiet, or relief--the sense of a weight or cloud lifting. About 15 seconds later, they spoke of an increased awareness, interest, and sense of connectedness with people in the room," Dr. Lozano said.

After 1 week of stimulation, eight patients responded and one was in remission. But, according to the published study, some of this initial benefit could be attributable to the microlesion effect, "commonly observed in Parkinson's disease where the mere insertion of a DBS electrode can produce transient clinical benefits." By 2 weeks, the response rate had fallen to 30% (six patients), consistent with this theory.

Within 1 month, however, the treatment benefits had become more obvious. Mean Hamilton depression scores had decreased by 10 points. At 6 months, the scores had dipped another 3 points, at which time improvement plateaued. Sixty percent of the patients (12) were considered responders and 35% (7) were in remission.

By 12 months, 55% of patients (11) were responders and 7 patients were in remission or within 1 point of remission.

Patients who responded also experienced global improvements in mood, anxiety, somatic, and sleep scores. Mood improved the quickest, while the other symptoms rook longer. "The different response times of the various depression components suggest that the distinct symptoms of depression may be supported by different neural substrates," the researchers noted.

Functional brain imaging supported this theory, according to the study. Eight responders underwent positron emission tomography scans. There were "striking changes in cognitive and limbic brain areas, providing a biological basis for the observed improvements in depression," the investigators noted.

"We feel what is happening is that DBS not only turns down the activity in the SCG, but has remote effects on the regions it communicates with, resulting in these changes in cortical function, limbic structures, and the striatum," Dr. Lozano said. "We seem to be having an effect on the entire circuit that mediates depression."

The surgery was well tolerated, he added. Three patients had wound infections requiring hardware removal. One patient, who had experienced benefit, had the electrodes reimplanted and recaptured the clinical improvements. The other two had not benefited from the procedure, and the hardware was left out.

Dr. Lozano is a consultant for Advanced Neuromodulation Systems and Medtronic inc., companies that manufacture DBS components. He is also an intellectual property holder and licensor in the field of deep brain stimulation.

ARTICLES BY MICHELE G. SULLIVAN

Mid-Atlantic Bureau