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.
Major study of deep brain stimulation for treatment-resistant depression fails, is shut down by FDA http://t.co/JhfAHIxqL0
— Vaughan Bell (@vaughanbell) January 16, 2014
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.
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.
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