Brain Stimulation Methods for Treating Depression

Well into the 1970s, we psychiatrists believed that depression came from anger turned inward-and we acted on this notion. Psychiatrists spent countless hours trying to get depressed patients to talk about their anger. Enterprising psychologists and psychiatrists devised schemes to make such patients angry. As a medical student, I watched from behind a one-way mirror as a hospitalized depressed man built a tower of small blocks. When he had almost completed the tower, the "therapist" knocked it down. Undeterred, the man persisted and, as I recall, he never got angry. He continued to start the tower and seemed unconcerned when the psychiatrist whacked it down. But the anger theory captivated us-it came straight from Freud's paper "Mourning and Melancholia"-and the total lack of evidence that any of these therapies actually worked seemed trivial, barely worth mentioning. So patients endured our attempts to get at their anger until, for one reason or another, their depressions lifted. Gradually, drugs took over, and by the end of the 1970s, depression was a biochemical disturbance in the brain. Now a new paradigm for depression is coming into view. Fueled by 2 decades of brain imaging findings and, more recently, by brain stimulation therapies, neural circuits seem about to displace serotonin and norepinephrine as the source of melancholia. The brain imaging results, plentiful as they are, are difficult to interpret. If depressed patients are shown to have small hippocampi or reduced prefrontal cortical blood flow, does this cause the depression or result from it? Few of the neuroanatomic findings have been consistently replicated or are specific to depressive illness. But if a depressed patient gets relief from stimulation of a part of the prefrontal or cingulate cortex, not only is it fair to implicate that structure-or something connected to it-in the pathophysiology of depression, but also we may have a new and better treatment. At least this is what we're hearing from the advocates of the new stimulation therapies: vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS). ROOTED IN NEUROLOGY These stimulation techniques have more in common with the anger-turned-inward theory than it appears. First, both are firmly rooted in neurology: the anger-turned-inward theory was devised by a neurologist with a background in neuropathology and, likewise, the brain stimulation techniques were developed by neurologists and neurosurgeons. Second, as with the anger-turned-inward theory, more than a few psychiatrists are convinced that the stimulation procedures work-particularly VNS, to date the only stimulation technique that is FDA-approved for depression-despite the dearth of evidence in support of their effectiveness. VNS had an auspicious beginning. As Linda Carpenter, MD, associate professor of psychiatry at Brown Medical School and a VNS researcher, tells it, some patients with epilepsy who were participating in a clinical trial of VNS stayed at the same Gainesville, FL, hotel whenever they came into town for the study. A hotel clerk mentioned to one of the researchers, "I don't know what you're doing, but every time I see them, they get happier." This sort of serendipitous observation not uncommonly lies behind important treatment innovations: the discovery of the antidepressant properties of monoamine oxidase inhibitors (MAOIs), for example, arose from an observation not very different from the hotel clerk's; some patients being treated for tuberculosis with iproniazid, an MAOI, were noted to have elevated mood. But not all chance observations end in an effective treatment. Prompted by the hotel clerk's observation, 2 studies systematically addressed mood changes in epileptic patients treated with VNS. Mood rating scale scores did improve somewhat over a 12-week period.1,2 Then, an open clinical trial in treatment-resistant depressed patients showed that after 10 weeks of VNS, 30.5% improved.3 From then on, however, the evidence began to unravel. The only randomized controlled trial of VNS failed. This 12-week pivotal study compared VNS with sham VNS (stimulator not turned on) in patients with treatment-resistant depression (TRD), unresponsive to at least 2 treatment trials. VNS had no significant advantage over sham treatment.4 Then in a long-term follow-up study, patients with TRD received 1 year of VNS and were compared with a