The Corpus Callosum

VNS Therapy in Treatment-Resistant Depression: Clinical
Evidence and Putative Neurobiological Mechanisms

Charles B Nemeroff*,1,2, Helen S Mayberg2, Scott E Krahl3, James McNamara4, Alan Frazer5,
Thomas R Henry2, Mark S George6, Dennis S Charney7 and Stephen K Brannan8

Currently available therapeutic interventions for treatment-resistant depression, including switch, combination, and augmentation strategies, are less than ideal. Observations of mood elevation during vagus nerve stimulation (VNS) therapy for pharmacoresistant
epilepsy suggested a role for VNS therapy in refractory major depression and prompted clinical investigation of this neurostimulation
modality. The VNS Therapy Systemt has been available for treatment of pharmacoresistant epilepsy since 1997 and was approved by
the US Food and Drug Administration for treatment-resistant depression in July, 2005. The physiology of the vagus nerve, mechanics of the VNS Therapy System, and efficacy and safety in pharmacoresistant epilepsy are reviewed. Promising results of VNS therapy for treatment-resistant depression have been forthcoming from both acute and long-term studies, evidenced in part by progressive improvements in depression rating scale scores during the 1st year of treatment with maintenance of response thereafter. VNS therapy is well tolerated in patients with either pharmacoresistant epilepsy or treatment-resistant depression. As in epilepsy, the mechanisms of
VNS therapy of treatment-resistant depression are incompletely understood. However, evidence from neuroimaging and other studies suggests that VNS therapy acts via innervation of the nucleus tractus solitarius, with secondary projections to limbic and cortical structures that are involved in mood regulation, including brainstem regions that contain serotonergic (raphe nucleus) and noradrenergic (locus ceruleus) perikarya that project to the forebrain. Mechanisms that mediate the beneficial effects of VNS therapy for treatment resistant depression remain obscure. Suggestions for future research directions are described.
Neuropsychopharmacology (2006) 31, 1345–1355. doi:10.1038/sj.npp.1301082;

The vagus nerve is one of the twelve pairs of nerves that comes out of the brain and goes to some body part more or less directly, rather than going through the spinal cord.  The vagus nerve, in particular, runs through the neck and into the chest.  It does a wide variety of things, although none of its known functions has anything to do with emotional regulation.  The reason I mention that, is that I find it fascinating that electrical stimulation of a nerve could have such a  profound effect on something that does not appear to be related to the function of the nerve.

VNS therapy originated as a treatment for epilepsy that was refractory to treatment with medications.  Early studies indicated that some patients with both epilepsy and depression experienced improvement in their depression as well as their epilepsy.

In order to undergo this treatment, patients have to have a pacemaker-like device implanted in their chest.   It costs about $15,000.  For these reasons, it is not something that is undertaken lightly.  

It is not a quick fix, and it does not always work.  In the first ten weeks, about 30% of patients have at least a 50% reduction in symptoms, and about 15% experience remission.  The mean time to response in 48 days.  (Response is defined as a 50% reduction in symptoms.)

After one year, the response rate is 44%.  After two years, the response rate is 42%.

In is important to note, however, that patients do not need to have a response in order to benefit.  At first, that seems like a nonsensical statement.  However, remember that the word response is used here in a technical sense.  Even a 25% reduction in symptoms can make a big difference in a person's life.  It could make a difference between being employed or being on disability, or being married versus getting divorced.  




The article is full of information about the neurobiology of VNS treatment.  You can probably tell already what the conclusion is :

As with epilepsy, the mechanisms by which VNS therapy may benefit treatment-resistant depression are presently unclear.

Even so, there is a lot that is known, and the article lays it out pretty well.

Perhaps just as interesting from a public-interest perspective is the fact that one of the recipients  of the treatment, Charles E. Donovan III, has written a book about his experience, Out of the Black Hole.  Also, one can get additional perspective by reading the reader comments on the Amazon page for the book.  He has a blog here.

The Nemeroff article ends with some suggestions for future research.  I found that section to be a little disappointing.  Although they have good suggestions, the suggestions mostly are oriented toward optimizing the effectiveness of the treatment.  As a clinician, though, I do not see a suggestion for what I anticipate would be my most frequent problem.  

In considering what patients to refer for consideration of VNS treatment, I would want to know this: does the presence of personality disorder or substance abuse disorder influence the probability of treatment response?

If the safety profile and clinical effectiveness are borne out in widespread use, VNS treatment will be an important advance.  It also has the potential to teach us a great deal about the pathophysiology of depression.  I suspect that there will be advances in the basic sciences of neurobiology, and physiology in general.  But even a full understanding of those fields will leave us with the nettlesome problem of how to select patients appropriately.

They do offer one suggestion in that area:

Can predictors of response to VNS therapy in depressed patients be identified by functional imaging or genetic studies?

That would be helpful, but frankly, I do not have much hope that it will pan out.  Based upon our experience so far with attempts at treatment matching, I am fairly sure that in the near future, patient selection will be on clinical grounds only.  The most difficult decisions will be for those patients with depression and personality disorder, or depression and substance abuse.