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Deep Brain Stimulation for Major Depression: Miracle therapy or just another treatment?

The views expressed are those of the author and are not necessarily those of Scientific American.

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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

Scicurious About the Author: Scicurious is a PhD in Physiology, and is currently a postdoc in biomedical research. She loves the brain. And so should you. Follow on Twitter @Scicurious.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. Binkley 2:02 am 01/9/2012

    Interesting – in my case various types of SSRI were little help (one made my depression worse) so I wonder if that would be a negative indication for such surgery, if seratonin regulation is the implied mechanism?

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  2. 2. scicurious 8:47 am 01/9/2012

    Binkley: no, in fact all of these patients had SSRIs fail as well (they are generally first line treatment). The only thing the studies have shown with regard to serotonin is that it requires an INTACT serotonin system, and induces serotonin release. Just because someone doesn’t respond to SSRIs does not mean they don’t have an intact serotonin system, it’s very likely that you do.

    In my opinion, I think the increases in serotonin are part of a possible mechanism, but I think it’s far more complicated than that, and may bring in things like neurogenesis, stress responses, inflammation, etc, of which serotonin plays a role. It just happened to be the role scientists detected first.

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  3. 3. Armagnac 1:26 pm 01/9/2012

    I recently joined one of these trials and had the DBS implanted. (I am not part of the most recent publication data.) I think this will always be a treatment of last resort, because being awake during all-day brain surgery is never going to be someone’s first treatment choice.

    It is my understanding, as limited as it is, that BA25 is overactive in depressed patients. Somehow the stimulation increases the inhibition of this area. Does this imply that neurogenesis is not the mechanism of action, since the goal is actually to reduce activity?

    There did seem to be initial antidepressant effects of the surgery itself in my case, probably due to inflammation, but they wore off rather quickly. The possibility of plasticity playing a role are now being studied through the follow-up process, brain rehab of a sort.

    I believe they are trying to learn, with every test they have, if there is a way to determine in advance who will respond. However, the most recent data does indicate that if the implant was kept activated, everyone was a responder (>50% decrease in symptoms) at two years. It may take a really long time, but it does seem to help eventually. And so far none of the people who went into remission had a relapse, other than if the stimulation stopped, due to a dead battery for example.

    Personally, even a less than 50% response would be better than everything else I have tried. People like me in the trial have exhausted every option we have, and don’t have much hope for spontaneous response or remission otherwise.

    The key so far is that this does appear to be safe in the long term. I’d like to say that nobody got worse, but I’m not sure that would even be possible given the severity of the depression we are discussing.

    Obviously I have been following this story quite closely, and your discussion is one of the best that I have read on this topic. Thank you.

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  4. 4. scicurious 1:43 pm 01/9/2012

    Armagnac: Thanks so much for stopping by! It’s really wonderful to hear from someone who is currently undergoing the treatment, and I sincerely hope that you are seeing improvements in symptoms. I got the impression the surgery was extremely arduous, as there is both the original brain implantation and then a subcutaneous placement for the lead and stimulator, is that performed on a separate occasion?

    You are correct, the idea is to decrease stimulation in this area (there is a mixture of glutamatergic and GABAergic neurons here, and I’m not sure whether the inhibitory or excitatory neurotransmitter release dominates). However, inbhition of an overactive area does not necessarily mean that neurogenesis is not implicated (though this may be another mechanism, we don’t know). Circuits are extremely complicated in many areas of the brain, and the inhibition of an excitatory circuit could, for example, relieve the active inhibition of ANOTHER circuit, allowing for more activity. Until we have full knowledge of the circuitry in this region, both where the signaling comes from, where it goes to, AND how other systems feed back upon it, we can’t really say what effects the inhibition if having on the brain itself.

    The most recent data do indicate that responders did remain responsive after two years, but only those responders who INITIALLY responded (several did not respond at all to initial implantation, and two did get worse, unfortunately). So of their 60% that responded at 1 month, all of them retained a response at 2 years. This is indeed a wonderful response, but it also makes me wonder, as there is still some resistance, whether we still aren’t getting at the underlying mechanism. It’s a difficult question, the symptoms of depression are so disparate that we could be dealing with really several different mechanisms, all of which manifest as “depression” as we see it in the clinic. This may mean that we have to develop different treatments for different underlying mechanisms, as we discover what those mechanisms are. I definitely think that more clinical and basic studies are needed to really identify what DBS for depression is affecting and in what ways.

    I am not a clinician, just an interested scientist, but I would be very interested to hear how your treatment is progressing. I hope that it goes well. Thanks again for reading and best wishes.

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  5. 5. herb1008 11:24 pm 01/9/2012

    Hi Scicurious,

    You state “…or just another therapy?” leading one to believe that “just another therapy” is not important to this unique population of seriously ill patients that have suffered, anguished and attempted suicide over decades.

    The point being whether or not DBS exhibits outstanding efficacy percentages is not as important as the fact that it offers hope and the additional fact that some have already benefited when decades of conventional therapies and hospitalizations have proven ineffective.

    As controversial as VNS (Vagus Nerve Stimulation) has proven to be, those patients who have responded to VNS have maintained long-term efficacy and remissions. The less than stellar results from rTMS (Rapid Transcranial Magnetic Stimulation) also have exhibited patients that have benefited longer term when no other conventional therapies have proven efficacious.

    As a very, very long time support person and health care advocate for my spouse, I couldn’t care less whether the results are a miracle or just another therapy. What was important to us after some 36 years is that we found a neuro-modulation therapy (VNS) to work like no other therapy even though one might consider it “just another therapy”. For us; we consider it remarkable.

    The point being as my spouse and I approach 5 decades together we’ve learned that there are no guarantees of efficacy, remission, miracles and/or cure as it relates to any of the mental health therapies and worse yet is the potential for serious side-effects. What are important to the patient and their loved ones are options. I have through the years continued to advocate for patient and/or support person education, newer treatments while also encouraging hope and persistence. Early on I coined a phrase “The Trial and Error Approach to Wellness” which I firmly believe is still applicable today and those patients considered to be the worst of the worst are faced with trial and error treatment approaches whether it be the various talk-therapy disciplines, holistic, medications, ETC, VNS, rTMS and the more recent DBS etc.

    These past 12 years my spouse has been almost continuously depression free and our quality of life vastly improved.

    So, “just another therapy” might be a life-saver for someone and is certainly far more important than no therapy at all.


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  6. 6. scicurious 6:31 am 01/10/2012

    @herb1008: I do not intend by “just another therapy” to imply that it is of no use. Indeed, my entire post concerns the fact that I think DBS may be of great use indeed. I just don’t want people to consider it to be a miracle therapy when we still know so little about the mechanism, and while the recoveries are remarkable, they are not even close to 100%. I realize that what is important to patients are that the therapies work, but what is important for an eventual cure is that we understand mechanism. I think it is possible to look at both of these angles with coming research.

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  7. 7. alpha-o 2:51 pm 01/16/2012

    I, too, am currently enrolled in a clinical trial of DBS for depression. Fortunately, 2.5 years post-op, I am doing remarkably well. For the first time in 20 years, I am in remission.

    I appreciate the thoughtful and educated posts on this site and want to add something equally substantive. While I am happy to share particulars of my experience – for example, (and to answer your question), I had surgery to implant the electrodes in my brain AND to implant the IPG units in my chest all in one day – at this point I will just make the general comment that research and treatment for mental illness are grossly underfunded. I realize that I am probably preaching to the choir here, but depression is a real illness & human tragedy. Yes, let’s try to understand the mechanism by which DBS can work.

    One piece I might be able to add that I don’t think has been mentioned yet is that results take time to achieve. I noticed some immediate positive effects from electrode implantation & activation. However, it took about 6 months of stimulation for me to notice any substantial (and probably measurable) improvement. I know other people enrolled in the trial I am in had the same experience. Unfortunately the blinded phase of the trial was only 4 months long, so this particular trial probably did not yield a statistically significant result.

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  8. 8. jimmaps 9:46 am 02/24/2012

    Does anyone know about a trial about dbs for depression in europe or preferably in the Netherlands?

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  9. 9. mgcorde 7:30 pm 03/31/2012

    Hello Scicurious. Great info in this article. I need your help. How can I get in contact with Armagnac?

    I am needing to get into a DBS trial for MDD ASAP.

    I was diagnosed in 1988 w/depression so you can just imagine my resume of treatments/meds/etc. I already live in my daily HADES & that’s bad enough so I can’t kill myself [it's against my religion anyway & I am NOT a quitter].


    Not a Quitter [aka mgcorde]

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  10. 10. SAH61 9:10 am 09/8/2012

    Actually, Armagnac is right. The latest well-designed studies in fact show that ~90% of patients responded (>50% in HAM-D scores) at 2 years post-op.

    Some of the older studies did not follow patients that long, or else only followed early responders that long. Also, the technology has been improved since the older studies. The target has been better identified, and the electrodes are often narrower. The currently-identified response rate is, in fact, roughly 90% after two years.

    You ought to consider that someone in a Deep Brain Stimulation study–which requires numerous meetings with the best-informed research psychiatrists and neurosurgeons in the field–might have a better idea of the current DBS statistics than you do.

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  11. 11. dtknal 4:21 pm 10/11/2012

    My wife has just commenced a DBS trial in the UK and is now one month on after surgery of the implant device. The surgery was completed totally under general anaesthetic but was a lengthy process lasting approx 8 hours. For her, DBS was a light at the end of the tunnel offering the potential for some relief. It would be great if the device is turned on and she got instant relief but unfortunately it doesnt work that way. Just the start of the journey, but hoping and praying that the DBS provides relief.

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