Doctors long have struggled over what to do with severely depressed patients who don't respond to treatment. Give them more medications that haven't worked so far? Recommend more talk therapy or another round of shock treatment?
Here's a new idea: open up a depressed head, find the brain parts that aren't working, and fix them with electricity. It's not all that far-fetched. Earlier this month, the Food and Drug Administration gave a medical device manufacturer the green light to recruit patients for a large-scale clinical trial of an electrode implanted deep inside the brain to alleviate severe depression. As invasive and Frankenstein-ish as it may seem, deep brain stimulation, as the method is called, may offer real hope for the 20 percent of depressed Americans whom Prozac can't help.
Anti-depressant drugs carpet-bomb the entire body. Electroconvulsive therapy jolts the whole brain. Deep brain stimulation aims to pinpoint the malady. Neurosurgeons drill through a patient's skull, place the DBS electrode's eight contact points directly on the trouble spots and connect them to an electrical current from a pacemaker embedded in the chest. This allows doctors to rev up sluggish areas or calm overactive regions.
DBS has been used for a decade to control symptoms of Parkinson's disease. Using it to treat depression poses a different challenge. While neurologists may have found the region of the brain that controls tremors, they haven't yet confirmed where those magic buttons are for mental illness. How do you isolate something as all-consuming as depression—the grief, irritability, self-defeating thoughts, and irregular interest in food, sex, and sleep—in a few millimeters of gray tissue?
Despite the obstacles, the results of small studies testing DBS on depressed patients are promising. For example, researchers are honing in on the region known as the subgenual cingulated, which scans show is overactive in the brains of depressed patients and subsides when they undergo ECT or take antidepressants. (The same area lights up when nondepressed people experience extreme sadness.) Critics caution that highlighted areas on a scan don't necessarily correspond to the loci of depression, yet early research shows that depressed patients feel better when the area is continually stimulated. One such study of brain implants, by Emory psychiatric neurologist Helen Mayberg, found striking and sustained improvement in four of six patients. They reported feeling suddenly calm, aware, and interested in social activities. Some talked more spontaneously, louder, and with more emotion. Others said the colors in the room became brighter and details were more vivid.
Another research team is targeting a different but nearby part of the brain—the network of nodes in the frontal lobe and base of the thalamus and basal ganglia, where emotion, attention, and anxiety are believed to converge. In a recent study for another device manufacturer, researchers from Brown University and Cleveland Clinic found that five of 10 patients treated with DBS between 2003 and 2006 showed a 50 percent reduction in the severity of their depression one year later. Patients said they had less anxiety, more energy, and felt more connected with themselves and people around them. One said simply, "The fog has lifted." The researchers are waiting for approval to start enrolling patients in a bigger trial later this year.
Despite this early encouragement, there are reasons to be cautious. Parkinson's researchers were able to induce and treat tremors in animals before embarking on DBS in humans. But animal research on depression doesn't really work, because we don't know how to measure animals' mental states. That means human trials from the outset. The two major ones proceeding so far are being sponsored by companies—St. Jude Medical and Medtronic—that make the implants and so have a vested interest in the results. The legacy of psychosurgery is not exactly reassuring, either. DBS may be a far cry from the days when lobotomies robbed patients of the ability to feel emotions like love and compassion. But not long ago, patients receiving ECT suffered serious memory loss.
It's also unsettling that scientists can't account for why the patients in the small initial studies felt better—or why some showed dramatic changes and others improved only slightly or not at all (although no one got worse). Theories abound about whether the DBS voltage changes the firing pattern in the brain or affects a larger depression "circuit" that other treatments can't reach.There are no data on the long-term risks of continuous stimulation, and it's uncertain if the results could be replicated on a larger scale. "This is certainly not yet ready for prime time," says Mayberg, who has enrolled 20 more people in her study. DBS also carries a 1 percent to 2 percent risk of intracranial hemorrhage and a 5 percent to 10 percent risk of infection or a malfunctioning pacemaker. At the highest voltage, some patients temporarily felt lightheaded or mentally slow. Also, there's the potential for brain damage from gliosis (the brain's version of scar tissue), which can develop around the contact points.
At the same time, autopsies of Parkinson's patients who received DBS implants revealed no significant changes in the areas around the electrode contacts, according to Cleveland Clinic neurosurgeon Dr. Ali Rezai. He also points out that his depressed subjects tested the same in terms of cognitive functioning before and after getting implants. In some cases, the current even improved their memories. (Again, scientists don't know why.)
On balance, the FDA is right to move forward with this precarious research. The history of antidepressant drugs is full of examples of treatments that scientists didn't—and still don't—precisely understand and that nonetheless have brought relief to millions of people. And unlike other neurostimulation therapies for depression on the market or in development, the brain pacemaker has a track record. Some 40,000 people worldwide have undergone DBS, mostly for Parkinson's and other movement disorders. Researchers testing it for mental illness say they follow strict protocols by admitting only subjects who have tried and failed to respond to numerous rounds of drugs, psychotherapy, and ECT. In other words, like a lot of people willing to try experimental treatments, these patients have less to lose.
None of this means, however, that DBS is likely to be used to treat depression on a wide scale. Researchers currently are looking for brain markers that might flag which patients would respond best to it. The treatment also isn't a cure-all, and patients may need to supplement it with more traditional talk therapy. Meanwhile, neurologists are exploring the use of brain pacemakers to treat drug addiction, anorexia, obesity, Tourette's syndrome, and obsessive-compulsive disorder. We have to simultaneously become more comfortable with poking around in people's brains without letting ourselves forget just how mysterious and delicate this all is.
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