This week, a team of researchers from the University of Toronto published a paper in The Lancet describing the results of a small study using deep brain stimulation (DBS) to treat severe/chronic anorexia nervosa. Major news outlets, including the BBC, reported on the findings. A few people emailed and messaged me asking me to do a post about it (which is cool! I love it!). So here it is.
DBS is a surgical procedure that involves implanting an electrode that delivers electrical signals to the brain. DBS is used to treat Parkinson’s disease and other movement disorders with good success, and has recently been implicated in the treatment of OCD and depression as well. (This is a pretty good video explaining how DBS works for movement disorders. There’s lots of information online about how DBS works, so I won’t go into detail here.)
This is not the first time that DBS has been used to treat anorexia nervosa patients (and I actually remember hearing about this when I was in undergrad, a few years ago). There have been two case reports and one study of acutely ill adolescents with the disorder. This study, however, assessed DBS in six treatment-refractory AN patients. Since this is a phase 1 pilot trial, the major goal was to evaluate the safety of the procedure and identify side effects.
Patients had to between the ages of 20-60 and show a pattern of chronicity or treatment resistance. I’ve included the inclusion and exclusion criteria and a table describing the demographic characteristics of the patients below (Click on image to enlarge).
(Just FYI: BMI values are mentioned.)
- Female or male patients aged 20–60 years
- Diagnosis of anorexia nervosa, restricting or binge–purging subtype, as defined in the Diagnostic and
- Statistical Manual of Mental Disorders (DSM-IV-TR)
- Chronicity or treatment resistance shown by some orall of:
- A pattern of 3 years’ duration of relentless unresponsiveness to repeated voluntary hospital admissions, characterised by failure to complete treatment or immediate weight relapse after treatment
- A pattern of increasing medical instability, accompanied by refusal to participate in or a pattern
- of poor response to intensive expert treatment and increasing medical acuity, lasting at least 2 years and including at least two episodes of involuntary feeding
- A pattern of chronic stable anorexia nervosa that has lasted at least 10 years
- Able to provide informed consent
- Able to comply with all testing, follow-ups, and study appointments and protocols
- Any past or present evidence of psychosis
- Active neurological disease such as epilepsy
- Alcohol or substance dependence or abuse in the previous 6 months, excluding caff eine and nicotine
- Any contraindication to MRI or PET scanning
- Likely to relocate or move during the study’s 1-year duration
- Body-mass index less than 13
- Presence of cardiac arrhythmias or other cardiac, respiratory, renal or endocrine disorders, as a result of
- anorexia nervosa or not, that will result in substantial risk from a surgical procedure
(Honestly, I’m not sure why patient 4 was included…)
Lipsman et al selected a region called the subcallosal cingulate as a target for DBS. Their reasons were as follows:
- “imaging studies show similar patterns of activity in the subcallosal cingulate region and in its afferent and efferent projections in patients with anorexia nervosa as are seen in patients with depression;”
- “anorexia nervosa and mood and anxiety disorders are often comorbid, with similar anatomical structures and circuits implicated”;
- “subcallosal cingulate DBS improves symptoms in patients with treatment-refractory depression and reverses cerebral metabolic abnormalities in dysfunctional limbic circuits.”
1. BMI. Below is a table and a graph describing the BMI changes of the six patients during the course of the study. “Baseline” was taken as the average BMI in the 5-7 years prior to the study, assessed through doctors’ notes, an interview, and the patients’ diaries.
The BBC reported that “three people were able to gain weight and had improvements in their overall mood after undergoing the procedure.” But, when you look at the graphical representation of the table above, one thing becomes immediately clear: what three people? I only see two people with significant improvements in their BMI (Patient 1 and Patient 5).
Also note that the preoperative BMI was substantially higher than the baseline BMI (from a mean of 13.7 to 16.1). This is because patients 1 through 5 were attending inpatient treatment immediately prior to the onset of the study, which resulted in some weight gain. There was no mention of whether this treatment, or any other treatment (psychotherapy, nutritional counselling) was continued or initiated during the following 9 months post operation. (Only that no changes were made to medications in the three months following the procedure.)
I only found this bit of information in the press release:
Furthermore, four of the six patients also experienced simultaneous changes in mood, anxiety, control over emotional responses, urges to binge and purge and other symptoms related to anorexia, such as obsessions and compulsions. As a result of these changes, two of these patients completed an inpatient eating disorders program for the first time in the course of their illness.
This is a confounding factor. How do we know the effects were due to DBS and not the inpatient treatment? How do we know DBS helped them complete treatment, given that 4/5 patients receiving inpatient treatment experienced weight gain as a result of it?
In fact, because there was no control group, we really can’t comment on efficacy at all. All we can say is that DBS has potential, it is promising. There’s nothing wrong with that, and indeed, the intent of the authors was to “offer this procedure only to patients who might be expected to continue with a chronic illness or die a premature death because of the severity of their illness.” It would be unethical to withhold treatment we know has some efficacy in favour of an experimental procedure. But, it means that we need to be cautious in our response to the findings.
2. Mood. On the whole, there were improvements in mood, as assessed using various depression, anxiety, and obsessive-compulsive questionnaires. The two patients that experiences the most improvement in their BMI also showed the most significant reduction in scores on the various questionnaires (some patients showed no improvements at all).
There are two problems here, though:
- Lipsman et al only show the psychometric data up to the sixths month post-op. What happened to data for the ninth month? The study followed-up on the BMI for 9 months after the operation… what about mood assessments? That’s fishy. It makes me wonder if the data wasn’t ideal and so they just didn’t include it in the paper (which happens all the time, unfortunately).
- Regression toward the mean (which is true for the BMI, but less so given that baseline BMIs were supposedly the average of the last 5-7 years). Basically, most people seek treatment when they are at their sickest. It follows, then, that the only way forward is to improve. Perhaps the improvement in the scores is not due to the DBS (and we can’t tell, because there’s no control group) but merely to the fact that the scores observed prior to the operation were exceptionally poor, even for these patients, and usually they score somewhere in the range observed 6 months after the operation. Until we do controlled studies, we don’t know.
3. Brain imaging. Interestingly, the changes observed in the patients mimic the changes seen in treatment-resistant depression patients treated with DBS. In addition, there was a decrease in metabolic activity in the insula, a region that has been heavily implicated in current models of anorexia nervosa. There was also an increase in metabolic activity in another brain region, the parietal lobe. However, the clinical correlates of these changes (as far as I can tell) are not completely clear (though there are tons of pet theories and ideas).
4. Adverse events. Below is a table of the adverse events experienced as a result of the operation:
IMPLICATIONS & FUTURE RESEARCH
There are tons of implications, but I’ll just briefly cover some (and leave the rest for the comments section). Well, first: it is promising. Given how difficult it is to treat chronic and treatment-refractory anorexia nervosa, I welcome any new promising treatments.
The fact that this is not something that can be easily scaled up (few places in the world do DBS surgeries, Toronto being one of them, and then there’s the issue of cost and insurance coverage) might not be a huge problem if it is used only in a limited number of very treatment-refractory cases. But our goal should continue to be: to treat eating disorders at the earliest possible point and to focus on non-invasive treatment approaches that can be easily scaled-up. If this works, I think it should be a last resort treatment.
In the discussion, the authors noted that for these patients DBS might improve their mood and behaviours to a point where they can engage in standard treatments “that are heavily weighted toward psychotherapy.” The idea, then, is not that DBS itself is the only treatment or cure, but that it enables the patient to finally engage in treatment (“a food-in-the-door technique”). This makes perfect sense to me, and I think it is a worthy goal in its own right.
I’m not well-read on the use of DBS in neuropsychiatric disorders. If there’s clear evidence it works, that’s good, even if its effectiveness is limited to specific cases. Still, my initial hesitation has to do with the fact that in Parkinson’s disease, we have a clear understanding of what’s going wrong (the death of dopaminergic neurons in the substantia nigra), though even there there’s controversy about what DBS is actually doing and how it works. For complex neuropsychiatric disorders like OCD, depression, and anorexia nervosa, we simply can’t point to a specific brain region and go “Aha!” Still, I realize we don’t know how many of the drugs out there on the market work, so, perhaps my hesitation is not justified.
Ultimately, though, I think we need to be extremely cautious with our initial reactions to the findings in this study. I’m a bit worried about the media attention this small pilot study is receiving. Let’s reserve the excitement and optimism for the future, when we know the results of blinded, sham-stimulation controlled experiments.
Lipsman, N., Woodside, D., Giacobbe, P., Hamani, C., Carter, J., Norwood, S., Sutandar, K., Staab, R., Elias, G., Lyman, C., Smith, G., & Lozano, A. (2013). Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial The Lancet DOI: 10.1016/S0140-6736(12)62188-6