During the third day of the American Psychiatric Association 2008 annual meeting in Washington, DC, neurologist Helen Mayberg, MD, described targets for deep brain stimulation of treatment-resistant depression; distinguished neuroscientist Solomon Snyder, MD, discussed the significance of historical scientific advances that have led to current pharmacologic treatments and potential clinical applications of new discoveries; and CEO C. Thomas Caskey, MD, described the influence of genetic advances on diagnosis and treatment of disease.
Deep Brain Stimulation for Treatment-Resistant Depression
Deep brain stimulation can successfully relieve intractable depression, according to the results of a pilot study presented at this meeting by Helen Mayberg, MD.
Dr. Mayberg, Professor of Neurology and Psychiatry, Emory University, Atlanta, Georgia, explained that our growing understanding of the neurobiology of depression led to the selection of the subgenual cingulate region (Brodmann area 25) as an appropriate target for deep brain stimulation of treatment-resistant depression.
Dr. Mayberg observed, "With the aid of functional imaging with PET scans, we are fundamentally getting close to learning about the core areas that are critical to mood modulation. There is a reciprocal metabolic relationship between the cingulate and the frontal cortex. With intense negative affect, the cingulate is activated on PET imaging and the frontal lobe is turned off. With recovery of depression, the cingulate activity decreases."
Other features of the subgenual cingulate region that suggest that it might be a successful target for deep brain stimulation are its many connections to other areas of the brain implicated in mood control, such as the medial hypothalamus, (which has interneurons that regulate corticotrophin-releasing factor), dorsal raphe (serotonin), periaqueductal gray matter (pain), amygdala (emotion), and hippocampus (memory).
A pilot study of 6 patients (3 men, 3 women; mean age, 46 years) who received deep brain stimulation for intractable depression resulted in 4 patients who had a "striking and sustained" remission. Prior to enrollment in the trial, all of the patients had failed medical treatment, 5 had failed electroconvulsive therapy (1 refused), and all were disabled because of depression. Hamilton-17 scores decreased from a mean of 26 preoperatively to a mean of 4.3 at 1 year. Follow-up PET scans revealed a reversal from overactivity to decreased activity of Brodmann area 25. In addition, metabolic activity was decreased in regions directly affected by areas connected to Brodmann area 25. Conversely, the frontal cortex had increased metabolic activity.
Some patients had immediate relief after the stimulator was implanted and turned on. One patient described the sensation as, "It is as though I have been locked in a room with 10 screaming children with constant noise, no rest, no escape. Whatever just happened (when the stimulator was turned on), the children have just left the building."
Another patient said, "It is as if instead of being in the Grand Canyon, you are up on a ledge, no longer in a pit. You look around, and you know it is still 80 feet to where you want to be, but you are not in a hole anymore."
Many questions remain to be answered in regard to optimization of the technique of deep brain stimulation for depression, such as the duration of treatment needed and optimal stimulation parameters of pulse width and frequency. In addition to the subgenual cingulate, other brain regions may be suitable targets for deep brain stimulation, such as the anterior limb of the internal capsule, nucleus accumbens, thalamic peduncle, and cerebral cortex.
Dr. Mayberg has expanded her study to include 20 patients with a minimum of 1 year of follow-up; publication of these results is pending. Tractography has also been employed to learn more about the neuronal connectivity of Brodmann area 25. Dr. Mayberg estimated the cost of the device and procedure to be approximately $50,000, but emphasized that this treatment approach is still experimental.
Dr. Mayberg concluded, "The use of deep brain stimulation for intractable depression is going to require a very highly coordinated collaboration between neurosurgeons and psychiatrists because these patients will need behavioral rehabilitation with retraining to overcome the effects of years of living with depression."