Saturday, January 18, 2014

BROADEN Trial of DBS for Treatment-Resistant Depression Halted by the FDA

Webpage for the BROADEN™ study formerly run by St. Jude Medical


It's become mainstream these days to say that psychiatric disorders are neural circuit disorders. You can even read all about it in the New York Times! Cognitive training and neuromodulation (“electroceuticals”) are in, and pharmaceuticals are out, as explained by NIMH Director Dr. Tom Insel in a blog post about the Ten Best of 2013:
...if mental disorders are brain circuit disorders, then successful treatments need to tune circuits with precision. Chemicals may be less precise than electrical or cognitive interventions that target specific circuits.

One of the first to champion this position was Dr. Helen Mayberg and her colleagues, who conducted a small trial using deep brain stimulation (DBS) as a treatment for intractable depression (Mayberg et al., 2005). The technique has been heralded as a potential breakthrough in psychiatry, with $70 million in BRAIN Initiative funding going to DBS development. So a recent tweet announcing the failure of a major clinical trial garnered a lot of attention.



The December 13, 2013 issue of the Neurotech Business Report had the scoop:
The news that St. Jude Medical failed a futility analysis of its BROADEN trial of DBS for treatment of depression cast a pall over an otherwise upbeat attendance at the 2013 NANS meeting. Once again, the industry is left to pick up the pieces as a promising new technology gets set back by what could be many years.

It’s too early to assess blame for this failure. It’s tempting to wonder if St. Jude management was too eager to commence this trial, since that has been a culprit in other trial failures. But there’s clearly more involved here, not least the complexity of specifying the precise brain circuits involved with major depression. Indeed, Helen Mayberg’s own thinking on DBS targeting has evolved over the years since the seminal paper she and colleague Andres Lozano published in Neuron in 2005, which implicated Cg25 as a lucrative target for depression. Mayberg now believes that neuronal tracts emanating from Cg25 toward medial frontal areas may be more relevant. Research that she, Cameron McIntyre, and others are conducting on probabilistic tractography to identify the patient-specific brain regions most relevant to the particular form of depression the patient is suffering from will likely prove to be very fruitful in the years ahead.

But it was hard to find any other information about the failed trial. I can't be sure, but I think this is the study in ClinicalTrials.gov A Clinical Evaluation of Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression. The sponsor is St. Jude Medical. The record hasn't been updated since March 2013.

BROADEN is a tortured acronym for BROdmann Area 25 DEep brain Neuromodulation.

The July 30, 2013 version of the BROADEN website is preserved at archive.org.


The BROADEN (BROdmann Area 25 DEep brain Neuromodulation) study is a study to evaluate the safety and effectiveness of deep brain stimulation in patients with a severe form of depression known as Major Depressive Disorder (MDD) who have not responded to multiple treatments. Stimulation to the brain is provided by a surgically implanted medical device called a deep brain stimulation (DBS) system. The system provides stimulation directly to an area of the brain known as Brodmann Area 25 (sometimes referred to as BA25). The study will build upon the depression work of a research team from the University of Toronto, led by neurologist Helen S. Mayberg, M.D. and neurosurgeon Andres Lozano, M.D., PhD, FRCSC.

On January 10, 2014 an Anonymous commenter at DBS Trial1 said:
Regarding the Broaden Study, I'm not writing it off entirely but things aren't looking good. The FDA has put the brakes on the study so it will not enroll any new participants.
While the study is over a year old, the results so far are not encouraging and the device manufacturer is scaling back on monitoring and programming.
It appears that a possible major misstep was made, by not including fMRI mapping prior to implanting the electrodes. 

As Neurotech Business Report (NBR) mentioned, more precise mapping of the white matter connections of the subgenual cingulate (Brodmann area 25) may be essential (e.g., Johansen-Berg et al., 2008). To determine the anatomical connectivity of the subgenual cingulate region, those authors performed tractography (using diffusion-weighted magnetic resonance imaging) to trace the pathways mediating treatment response with DBS. They compared the connections of the subgenual ACC (sACC, blue/cyan) and the perigenual ACC (pACC, red/yellow).



Fig. 3 (Johansen-Berg et al., 2008). Connectivity-based parcellation of anterior cingulate cortex (ACC) and location of electrode contacts. Effective electrode locations are mainly localized within the sACC subregion.


A July 11, 2011 News Release from St. Jude Medical announced that the FDA had approved an expansion of the BROADEN Trial so that up to 20 different sites could enroll a total of 125 patients. There were only three sites originally Chicago, New York City and Dallas. Perhaps the trial resources were getting stretched too thin.

Another possibility raised by James Cavuoto
, Editor and Publisher of NBR, is that the FDA is too darn stringent in what it considers a treatment response:
Unfortunately, much of the progress in our understanding of DBS mechanisms in depression is potentially wasted without a vibrant installed base of patients and clinicians using and perfecting DBS therapies. ... In our view, the FDA needs to understand the vital importance of getting first-generation devices into the field and move away from arbitrary standards like improving symptoms by 50 percent in 50 percent of the population. The notion that if we can’t help everybody we shouldn’t help anybody has no place in medical science, particularly when you consider that neuromodulation therapies are working with the hardest-case patients who have not responded to other therapies.

Finally, there is the unfortunate possibility that DBS treatment in this patient group doesn't work as well as initially thought...

If anyone has additional information, please leave a comment.


Footnote

1 This blog [EDIT:  i.e., the DBS Trial blog] is written by an individual who for the past four years has had an implanted device for the treatment of intractible depression.


References

Johansen-Berg H, Gutman DA, Behrens TE, Matthews PM, Rushworth MF, Katz E, Lozano AM, Mayberg HS. (2008). Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression. Cereb Cortex. 18:1374-83.

Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. (2005). Deep brain stimulation for treatment-resistant depression. Neuron 45:651-60.


Further Reading:

A Depression Switch?

The Sad Cingulate

Sad Cingulate on 60 Minutes and in Rats

...But My Subgenual Cingulate Is Sad

Deep Brain Stimulation for Bipolar Depression

Subscribe to Post Comments [Atom]

19 Comments:

At January 19, 2014 7:48 AM, Anonymous Anonymous said...

Disappointing. I watched Dallas Buyers Club recently about the early stages of the HIV crisis and the development of HIV drugs (from the point of view of the patient, mostly). I'm wondering if something similar will happen in the DBS field, with some people starting to hack their own DBS systems to try things out by themselves, and in the process make faster progress.

 
At January 20, 2014 4:41 PM, Anonymous Anonymous said...

Psychiatrists can't even agree on what "major depression" is (and isn't. So this is not surprising.

 
At January 23, 2014 2:28 AM, Anonymous Anonymous said...

Neurocritic, after reading Footnote 1 I was wondering if, anecdotally, the DBS treatment seems to be working for you. Anything you would like to share? Any side effects? Any changes in effectiveness over the 4 years? Thanks.

 
At January 23, 2014 9:23 AM, Blogger The Neurocritic said...

Oh, I was referring to the DBS Trial blog... The writer there says, "I have been implanted with an EXPERIMENTAL electronic stimulation device - in my BRAIN - to reduce my depression. I've crossed the four year mark."

 
At February 05, 2014 6:55 AM, Anonymous Anonymous said...

As part of the Broaden Study, I can state that the side effects caused by the device were, at times, worse than the depression itself.

Those that conducted this study and anyone else who has jumped on the DBS bandwagon would do well to take a good hard look at those left in the wake of this failed study.

 
At March 14, 2014 1:44 AM, Anonymous Anonymous said...

I'm so curious to know more about this study and anything to do with the brain and its relation to all forms of mental illness. I was always skeptical about narrowing down something as complex as a mental illness to one "hotspot" in the brain but I recall the Lozano presentation on DBS for depression and the research indicated several areas had noticeably decreased activity while cg25 had high activity, so I followed along. I also recall a statement made by Mayberg herself, a couple actually; "for all we knew, we could turn on the contacts and make things worse" which pertains to your comment a great degree. She also noted that for those it doesn't work for, that, "they perhaps aren't the right patient" and that "we would have to understand the biology better". Which again is why I say I'm ever skeptical of narrowing it down to one thing, or place in the brain or structure. But I can't help but pervay upon the empirical facts we do have and think that perhaps we need do need to change how we rate and consider treatments as is stated in the Red lettered text. I should also state that I'm not so much a neuroskeptic rather, I'm near entirely neurocentric. I didn't come here to change minds or to upset but as the nature of good debate goes, to better approximate the truth. As my opinion stands I believe wonderful answers can be found within the brain but we must know more understand better. In the journey of 100 miles we've went about three inches and even those three inches have come from horrible mistakes. I assume most people here have heard of a patient by the name of H.M. who had his entire Hippocampus removed and could no longer translate recent events and information into lasting memory but his motor function memory was intact. Or consider Alzheimer's disease, a disease where one not only forgets but cannot comprehend the very nature of food, the concept of eating, where they are in time and space and we know that that is without a doubt do to neural malfunction and degeneration. Alzheimer's patients often suffer from depression and personality changes, aggression and isolation. So I believe the answers are primarily between our ears and that we shouldn't give up on the most complex thing in the entire universe.

 
At April 18, 2014 5:05 PM, Blogger anonymous said...

I AM PART OF THIS STUDY AND THIS DEVICE HAS NEVER WORKED FOR ME. I HAD FOUR GRAND MAL SEIZURES AFTER MY SURGERY, AND SPENT FOUR DAYS IN THE ICU THAT I DON'T REMEMBER. IT TOOK ME TWO DAYS JUST TO WAKE UP. I AM SORRY THAT I EVER GOT INVOLVED WITH THIS STUDY.

 
At April 20, 2014 1:59 PM, Blogger The Neurocritic said...

Anonymous of April 18, 2014 - I'm sorry that you and the earlier Anonymous of February 05, 2014 had such a terrible time. Your experience in particular sounds like medical malpractice.

 
At April 28, 2014 11:10 AM, Blogger anonymous said...

I agree with you in thinking this may be medical malpractice. I had to go home with my sister and she took care of me for 17 days because I couldn't function. When she found a good rehab facility, they wouldn't let me go. So I had no Rehab. I couldn't walk or talk right. I couldn't use my debit card or cell phone and I was still hallucinating. I am thinking of having a free consultation with an attorney.

 
At April 28, 2014 11:13 AM, Blogger anonymous said...

I have been thinking that this may be medical malpractice for a while. I had to go home with my sister and she took care of me for 17 days. I couldn't walk or talk right. I couldn't use my cell phone or debit card, and i was still hallucinating.
They said they would help with rehab, but when my sister found a facility for me to go to, they denied it. I am thinking of getting a free consultation with an attorney.

 
At May 01, 2014 11:09 AM, Anonymous Anonymous said...

I can't believe they didn't MRI the patients prior to surgery. (Is that accurate?)
I have had DBS for OCD and they used an MRI to place the electrodes accurately. This is absolutely standard in DBS treatment.

 
At May 01, 2014 11:33 AM, Blogger The Neurocritic said...

This press release, Precise brain mapping can improve response to deep brain stimulation in depression, describes a new paper from Emory, Case Western, and Dartmouth:

Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression, published in Biological Psychiatry.

"Results: Whole brain activation volume tractography (AVT) demonstrated that all DBS responders at six months (n=6) and 2 years (n=12) shared bilateral pathways from their activation volumes to (1) medial frontal cortex via forceps minor and uncinate fasciculus, (2) rostral and dorsal cingulate cortex via the cingulum bundle, and (3) subcortical nuclei. Non-responders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from non-responders."

 
At May 01, 2014 11:37 AM, Blogger The Neurocritic said...

Anonymous of May 01, 2014 11:09 AM - I believe that is the case, or at least this sort of probabilistic tractography was not done.

 
At July 20, 2014 6:34 PM, Anonymous mcan said...

I am part of the study. It DID work for me and MRI mapping was done prior and following my DBS surgery. The abject misery of severe, treatment resistant depression necessitates the need for vigorous, ongoing research in this area. Depression is a DEADLY disease and should be treated just as seriously as any other "physical" malady. Yes, there area always risks associated with groundbreaking medical treatments, but the rewards for those of us who suffer (as well as our loved ones) are immeasurable. Would we have the same objections to those who pioneer experimental treatments for cancer?

 
At July 20, 2014 6:50 PM, Blogger The Neurocritic said...

mcan - I'm happy to hear that the treatment worked for you. Thanks for letting us know. I wish you continued good health.

 
At August 12, 2014 3:40 PM, Anonymous Anonymous said...

Clearly the accuracy of electrode placement is key and the way in which this is achieved for Parkinson's disease is to do the electrode implantation by real-time MRI. With an MRI-compatible neuro-navigation device, the accuracy of placement is within 1 mm. I would never do an electrode placement any other way, and perhaps the variability in outcome is more attributable to outmoded placement technology than anything else.

 
At September 08, 2014 8:24 AM, Anonymous Anonymous said...

My wife is a participant of the Emory-Mayberg trial, implanted in 2011 (fMRI for analysis, MRI used for placement). For us, this has been a life changing event. After many years of frequent medicine changes, ECT, phsychotherapy, etc., all of which worked only briefly, my wife was at a point where her brain was non-functional: Speech was difficult, driving was impossible, relationships were unimportant, my wife was just a shell of the incredible person she once was. Then the implantation and the slow but steady return to life. After three years with DBS, the improvements continue, getting better with each passing month. I am not sure whether the connections in the brain continue to improve or whether my wife is able to work on the physchological issues now that the biological issues are greatly improved. Either way, my wife has her life back and she is immeasurably grateful for this technology and the trial at Emory.

Side Effects: None

Wishes: A rechargeable IPG. Currently, batteries last about 11 months and require (minor) surgery to replace.

A side note: I have always found it amazing that the public assumes that the brain is the only perfect organ. Other organs can be defective, but not the brain. Everyone agrees that Diabetes and Cystic Fibrosis have a biological cause, but it is controversial to say "mental illness" has a biological cause. The Emory DBS trial proves to me that there is indeed a significant biological component to depression.

 
At September 09, 2014 1:38 PM, Blogger The Neurocritic said...

Thanks for reporting on your wife's condition. I'm glad to hear that DBS has been so successful for her. I wish her continued good health.

 
At October 26, 2014 12:36 PM, Anonymous Anonymous said...

I am part of the Broaden Study and am in the 4 year follow up phase. I go in for a 6 month check in a few weeks. I'm definitely going to try to get more information about the study and what happens if they abandon this part or when it is over. The paperwork said they would turn it off or take it out at the end of the 4 year study. But in my opinion it has helped me. Yes, I have been hospitalized several times after the procedure but I am functioning much better than I was prior to the study. The objective measures may not show it but I know it has helped even just the slightest. I'll take that.
But I'm worried about the "what next." Have you heard of any updates since earlier this year?

 

Post a Comment

Links to this post:

Create a Link

<< Home

eXTReMe Tracker