Scientists disagree over whether a brain implant for treating the most depressed patients is ready for clinical testing.
One research group, led by Emory psychiatry professor Helen Mayberg, experimented with thirty patients who had developed a major depressive disorder unresponsive to Food and Drug Administration-approved treatments such as medication, counseling, and electroconvulsive therapy.
“These are late stage advanced disease patients,” said Steven Garlow, a psychiatry professor at Emory University and a co-author of a study published this June in the journal Frontiers in Integrative Neuroscience. “They’re kind of in deep freeze. They’re not engaged with their families, their careers.”
Implanting the patients with an electrode thinner “than angel hair pasta,” the researchers monitored the patients’ health for over a year, Garlow said. Once patients received the electrode, the first response phase involved subtle changes that friends and families of the patients often noticed more than the patients themselves. The patients’ faces became more expressive, and they engaged more with others. After ten to twelve weeks, they entered phase two, in which they experienced mood swings. But by six months, the patients’ moods stabilized and began to improve slowly and steadily, throughout years of observation.
“There’s this gradual improvement in mood, in outlook, in cognitive processes, that predictably develops over time,” Garlow said.
This experimental therapy is called deep brain stimulation (DBS). The electrode targets a part of the brain that is overactive in very depressed patients. It uses high-frequency pulses to reset the electrical circuit in that region, lowering its activity. The therapy is more subtle than electroconvulsive therapy, which shocks the brain to trigger seizures.
The three distinct phases of recovery are unlike the effects of FDA-approved medications for depression, which can show their effects in weeks. However, the patients involved were no longer responding to those medications, Garlow said.
But researchers disagree over how to interpret promising findings from early experiments, with the Emory group arguing for more basic research and another group moving forward with plans for clinical testing.
The first clinical trials, in which the patients were unaware of whether they received an active or a sham DBS implant, failed to show the same improvements in patients. “We found that there was no difference between active and sham (treatments),” said Harvard Medical School psychiatry professor Darin Dougherty, the lead author of the first reported clinical study of DBS therapy for depression, published last year in the journal Biological Psychiatry.
Another major trial, called BROADEN, involved multiple research groups but suspended its operation a year-and-a-half ago after an analysis showed the trial would not achieve the hoped-for effects, according to Dougherty. Clinical trials like these are necessary for FDA approval of a new treatment. The trial was testing St. Jude Medical’s DBS implant, which the Emory group uses for its research.
Garlow said that these medication-type clinical trials, with observation periods of sixteen weeks, are the wrong model to use for the new therapy in light of the Emory group’s long-term findings. However, he did not think it is time to begin new clinical trials of the device. “The approach we take is, ‘what does DBS do,’ not ‘does DBS work,’” Garlow said.
Dougherty, however, takes a different view. His group is moving forward with plans for new trials, while agreeing with the Emory group that a new clinical study would have to look at a longer time frame for response to the therapy. “We’ve been in the process for a long time of thinking about alternative trial designs,” Dougherty said. One would involve starting all patients with an active implant and then randomly turning off some of them to see how patients’ responses change.
Mayberg said in a September 17 lecture at the Massachusetts Institute of Technology that this study type, called a blind withdrawal, could work for future clinical trials.
However, she said that the focus should be on better understanding the detailed impacts of the implants on brain circuits. The implant stimulates neuron tracks which spread throughout the brain, and electrical changes in parts of the brain both near and far from the implant need more study. “Nobody has any business doing (clinical) trials until we get this worked out,” Mayberg said.