New data from a study of patients with treatment-resistant depression who underwent deep brain stimulation (DBS) in the subcallosal cingulate region (SCG or Cg25) of the brain shows that this intervention is generally safe and provides significant improvement in patients as early as one month after treatment. The patients also experienced continued and sustained improvement over time.

The data are reported in the online issue of Biological Psychiatry by scientists from the University of Toronto and Emory Emory University School of Medicine. The study began at the University of Toronto in 2002, led by Helen S. Mayberg, MD, and collaborators Andres Lozano, MD, PhD, neurosurgeon, and psychiatrist Sidney Kennedy, MD.

Mayberg is now a professor in the Department of Psychiatry and Behavioral Sciences and the Department of Neurology at Emory University School of Medicine. This clinical trial is the culmination of Mayberg's 20 years of research using brain imaging technology that has worked to characterize functional brain abnormalities in major depression and to identify the mechanisms of various antidepressant treatments.

A report on the first six patients in the study was published in the Journal Neuron in 2005. The new paper reports on an expanded sample of patients and an extended period of clinical follow-up.

DBS uses high-frequency electrical stimulation targeted to the specific areas of the brain involved in neuropsychiatric disease. Twenty patients received SCG DBS for 12 months. Twelve of 20 patients experienced a significant decrease in depressive symptoms (defined by a 50 percent decrease in the Hamilton Depression rating scale) by six months, with seven patients essentially well with few remaining symptoms (remission, defined as a Hamilton Depression Rating Scale score <8). Benefits were largely maintained at 12 months with continued stimulation. No long-term side effects were reported.

Each study patient was implanted with two thin wire electrodes (one on each side of the brain) in the white matter adjacent to SCG. The other end of each wire was connected under the skin of the neck to a pulse generator implanted in the chest -- similar to a pacemaker -- that directs the electrical current. The researchers regulated the intensity of the current according to the response of the patient. Only patients who were unable to get better with most other types of antidepressant treatment -- including medication, psychotherapy and electroconvulsive therapy -- were included in the study.

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"In previous studies using brain imaging, we found the subcallosal cingulate region was a key region in an emerging emotion regulation circuit implicated in major depression," explains Mayberg.

"We postulated that if stimulation worked for the treatment of other neurological disorders where abnormal function of specific circuits was well established, such as Parkinson's disease, then stimulation of the Cg25 region within this apparent depression circuit might provide significant benefit for patients with treatment-resistant depression."

The researchers were able to track the clinical response of the patients over a 12-month period using standard depression rating scales as well as various quantitative measures of behavior and general functioning, neuropsychological testing and scanning of both regional brain blood flow and glucose metabolism using positron emission tomography (PET).

PET imaging of these patients demonstrated that metabolic activity changed locally at the site of stimulation but also throughout the previously identified depression network, providing evidence that modulating the circuit and not just a single region was likely responsible for the antidepressant effects. "We see depression as a complex disturbance of the specific circuits in the brain responsible for regulating mood and emotions," Mayberg says. "We hypothesized that if DBS could locally modulate a critical central location within this mood circuit, such modulation would result in clinical improvement -- and it appears it does."

Mayberg initiated an expanded version of her Toronto study at Emory in 2007 with psychiatrist Paul Holtzheimer, MD, and neurosurgeon Robert Gross, MD, PhD, and with grant support from the Woodruff Fund, The Stanley Medical Research Institute and the Dana Foundation.

The new Emory clinical trial is tackling a number of unanswered issues including the testing of patients with bipolar II depression and refinement of the targeting and selection of the electrodes using new imaging techniques. The Emory study will enroll 20 patients and will be conducted over a period of at least three years.

The Toronto study was funded in part by a Distinguished Investigator Award from National Alliance for Research in Schizophrenia and Depression (HSM).

Reference: Biological Psychiatry published online July 2008 DOI: 10.1016/jbiopsych.2008.05.034