The idea of using deep brain stimulation for treatment of major depressive disorder is one that's been brewing for a while. Every so often I see another followup or report of a long-term study on deep brain stimulation. A followup came out recently in Nature News, documenting the long term success of a small clinical study. These studies are only going to get more press as deep brain stimulation treatment is investigated, and it's worth asking now: is this the miracle that depressed patients have been looking for? Or is it only another therapy, with another low chance of success?

Deep brain stimulation (DBS) involves the implantation of a small stimulating electrode into a specific area of the brain. It's not always for depression, doctors use DBS for treatment of other disorders such as Parkinson's and essential tremor as well. In all cases, a small electrode array of four individual electrodes gets implanted into the brain area of choice. A tiny insulated wire connects the array to an impulse generator, a battery powered device that will generate the stimulation. This is usually placed under the skin (usually near your collarbone), while the wire connecting the two runs under the skin as well, around your ear, and into the top of your head. Once implanted and turned on, the impulse generator will send either constant or intermittent stimulation to the electrodes at a specific frequency and strength, which will result in the depolarization of a local group of neurons near the electrode. The effects of the implant depends on where in your brain it is place. The devices can last for years (as long as you replace the generator batteries, anyway), and the implantation procedure is some pretty major surgery.

While we have been using DBS in Parkinson's patients for some time, the implications for depression are relatively recent. But a new treatment for depression is urgently needed. Right now, only 60% of patients will respond to the currently available treatments, including pharmacotherapies, cognitive behavioral therapy, and ECT. Many of these patients will not achieve a cure (in psychiatry we refer to this as 'remission'. It's never a full cure, but it is full remission of symptoms for a period of time). The other 40% do not respond well or at all, and this 40% represents many of the most desperate cases. But while DBS might represent a new possibility, we don't just want to go throwing people into brain surgery.

The earliest studies of DBS as a depression treatment began in rats. While many studies of pharmacological antidepressants have focused on brain areas like the hippocampus, studies using DBS have focused elsewhere, particularly on areas in the medial prefrontal cortex, specifically in humans Brodmann's area 25. This is an area that's sort of a "node" in a network, connecting cortical ("higher") structures with limbic regions and the brainstem. All of these structures have been implicated separately in major depression, so stimulating the 'node' in humans was thought to help depression by affecting the structures "downstream" of the node.

In rats, results have been promising. DBS in the ventromedial prefrontal cortex of the rat (a rat doesn't have Brodmann's area 25, this is the closest they've got), produces immediate antidepressant effects in tests like the forced swim test, which responds to clinically used antidepressants. And DBS causes large increases in serotonin in the hippocampus, and appears to be dependent upon normal levels of serotonin in rats, which brings in the serotonin model of depression, adding to some of the things we already know about how antidepressants behave in the brain.

Of course, these are rats, and rats don't actually HAVE a Brodmann's area 25. Moreover, no studies on DBS in rats have been performed in rodent models of depression (such as specific genetic strains or rodents exposed to stress). And the studies that have been performed in rats have necessarily been relatively short. Due to the desperation for treatments, and the relative safety of DBS (since doctors have been using it on Parkinson's patients and patients with chronic pain for years, it's fairly well developed), small clinical studies have begun using DBS in Brodmann's area 25 to treat depression.

The results at first can seem very striking. The only people who qualify for these studies are those who are fully treatment resistant. These patients do not respond to any pharmacotherapy, behavioral therapy, or even ECT, and many who qualified were hospitalized for psychiatric treatment. These are the truly desperate cases. But after implantation of the electrodes in area 25, a good number of them exhibited a truly remarkable recovery. 60% of the 20 patients implanted showed a reduction in depression score by 50%, taking them from extremely severe depression to a drastic improvement in daily function and quality of life, and some did achieve full remission of symptoms for a period of time. The responses were maintained relatively well, with those who responded continuing to respond 3 years later. For a disease where only 60% of a population will respond to other treatments, to have 60% of your most treatment resistant patients respond is a wonderful findings.

But while these findings are very promising, they shouldn't be hailed as a miracle quite yet. After all, 60% of these patients is still only 12 people. The other 8 did not respond at all, and one asked for removal of the electrode entirely. And while 60% of the patients did achieve a 50% reduction in symptoms at the first month, the symptoms did return, with only 30% maintaining their gain in function at three months. And not only that, the majority of the patients remained on pharmacotherapies for depression or antipsychotics both before and after surgical implantation. The surgery by itself may not be enough for these patients. Major side effects included nausea and vomiting (in 9 patients, may or may not have been related). Two patients eventually died in suspected suicides (which is NOT a side effect of the surgery, but rather is probably a lack of efficacy, suicide is the greatest cause of death in treatment resistant depression).

So where do we go from here? While I don't think DBS is a miracle, I DO think it's got some promise. 60% effect, even if it's not total remission, is a big difference in a population that is suffering this badly. It's certainly worth continuing the clinical trials to see if other people can benefit.

But I'm also becoming more and more intrigued over the mechanism of action. How is this working? In rats, it appears to be dependent on normal levels of serotonin, and stimulates serotonin signaling. Does it do the same in humans? How does it behave in comparison to other antidepressant therapies? Does it induce neurogenesis in rodents after prolonged administration as other antidepressant therapies do? What is the role of area 25 specifically and how does it modulate these other systems? So while I think it's important to continue clinical trials, I also think it's important to continue basic research. This procedure is striking, and though it's not a miracle, it could provide insight into how the depressed brain functions, and lead us, in the end, to a cure.

Lozano, A., Giacobbe, P., Hamani, C., Rizvi, S., Kennedy, S., Kolivakis, T., Debonnel, G., Sadikot, A., Lam, R., Howard, A., Ilcewicz-Klimek, M., Honey, C., & Mayberg, H. (2011). A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression Journal of Neurosurgery, 1-8 DOI: 10.3171/2011.10.JNS102122

Kennedy, S., Giacobbe, P., Rizvi, S., Placenza, F., Nishikawa, Y., Mayberg, H., & Lozano, A. (2011). Deep Brain Stimulation for Treatment-Resistant Depression: Follow-Up After 3 to 6 Years American Journal of Psychiatry, 168 (5), 502-510 DOI: 10.1176/appi.ajp.2010.10081187

Hamani, C., Mayberg, H., Snyder, B., Giacobbe, P., Kennedy, S., & Lozano, A. (2009). Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting Journal of Neurosurgery, 111 (6), 1209-1215 DOI: 10.3171/2008.10.JNS08763

Hamani, C., Diwan, M., Isabella, S., Lozano, A., & Nobrega, J. (2010). Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats Journal of Psychiatric Research, 44 (11), 683-687 DOI: 10.1016/j.jpsychires.2009.12.010

Hamani, C., Diwan, M., Macedo, C., Brandão, M., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A., Fletcher, P., & Nobrega, J. (2010). Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats Biological Psychiatry, 67 (2), 117-124 DOI: 10.1016/j.biopsych.2009.08.025