At APA's annual meeting in 2001 the buzz about new options for
treatment-resistant depression primarily involved "new molecular
targets" for pharmacotherapy—involving substances like glutamate,
the neurokinin-1 receptor that binds substance-P, corticotrophin-releasing
hormone, and neuropeptide-Y. Yet today, each of these "targets"
has proven disappointing as treatment options for patients with
At APA's annual meeting this year, the buzz focused on brain stimulation
devices and the promise they may—or may not—hold for those with
"The need certainly remains great," said psychiatrist Mark
Demitrack, M.D., vice president and chief medical officer of Neuronetics Inc.,
a company that is developing a novel brain stimulation device. In May
Demitrack chaired an annual meeting symposium—one of about a half dozen
presentations on treatment resistance—titled "Difficult to Treat
Depression: Looking for Our Keys Beyond the Light We Can See."
Demitrack is overseeing the development of a novel technique using
transcranial magnetic stimulation (TMS) as a potential treatment for resistant
depression and possibly other psychiatric disorders.
There is little dispute that a significant proportion of patients with
major depression do not respond adequately to current best-practice
treatments. While the definition of "treatment resistance" can
vary, the term is widely used to indicate a patient with depression who has
not responded to at least two courses of antidepressant medications from two
different classes. A treatment-resistant patient has also, by definition,
taken each medication in adequate doses for an adequate period of time, as
determined by FDA-approved labeling and practice guidelines.
Epidemiological data, Demitrack noted, indicate that of the more than 14
million persons in the United States with depression, only about half receive
treatment. Of those who are treated, fewer than half obtain an adequate
"The real issue in treating resistant depression [is] that
medications and electroconvulsive therapy.. .leave a significant gap [in both
treatment options and effectiveness] that remains to be filled for these
patients," Demitrack told Psychiatric News in a follow-up
He described a "treatment-resistance continuum" (see diagram
below) that is not adequately spanned by approved treatments. Medications, he
explained, whether given as monotherapy or polytherapy, fail to elicit an
adequate response for a significant proportion of patients and are associated
with a wide array of adverse effects. Electroconvulsive therapy (ECT),
although effective at relieving many patients' depression, often results in
cognitive changes such as amnesia. In addition, some patients experience
transient agitation or akathesia, which often resolves on its own or responds
Each of the brain stimulation modalities in development today, Demitrack
said, is based on "the long-standing question of whether the benefits of
electrical stimulation—as a method of treatment—could be separated
from the actual physical convulsion."
Demitrack continued, "We obviously have chemical methods of altering
the brain's electrochemical signals. The remaining question has been, Can we
provide electrical stimulation of sufficient intensity to cause neuronal
depolarization and keep it within a specifically targeted, local area of the
brain [in order to avoid seizure]? Now that we've shown we can do that
technologically, the question is, Can we achieve a therapeutic benefit [on the
The modern form of TMS was developed in 1985 by British physician Anthony
Barker, M.D., who developed the "focal magnetic coil." Barker was
the first to demonstrate in humans that it was possible to deliver a focused
electrical stimulation using strong magnetic fields that resulted in
functional activation of neuronal circuits in the cortex.
Numerous researchers have since confirmed the technique's ability to
produce localized stimulation, specifically of the brain's major mood
circuits—primarily targeted in the prefrontal cortex.
Research has also documented that the same type of stimulation can produce
limb movements when focused on the motor cortex and visual disturbances when
focused on the visual cortex.
The advantages of TMS include its non-invasive nature. To date, few if any
adverse effects have been associated with the treatment. Case reports from
patients undergoing MRI, which uses similar strong magnetic fields focused on
the body's anatomical structures, have indicated an associated antidepressant
effect, providing further support for the efficacy of the potential treatment
While TMS appears to be promising, it is still experimental and at best a
year and a half away from approved use in the clinical setting. Early clinical
trials have provided encouraging results, and Demitrack's company is
recruiting subjects for a large, multisite clinical trial. The company aims to
enroll 300 patients at 25 sites worldwide.
Neuronetics hopes to have results from its clinical trials early next year,
Demitrack told Psychiatric News. "We hope to have an
application for approval submitted to the FDA and have TMS on the market as
soon as late 2006."
The other brain stimulation modalities in development involve more invasive
technology and potentially more adverse events.
Vagus nerve stimulation (VNS), being developed by Cyberonics Inc., is the
closest to marketing approval in the United States; it is already approved for
use in European Union countries as an adjunctive treatment for depression in
patients who have failed to respond to at least four adequate courses of
VNS involves the implantation of a device similar to a cardiac pacemaker in
a pocket cut into the patient's pectoral muscle. The device is attached to
electrodes that are threaded under the skin and up to the neck, where they are
attached to the vagus nerve. The device delivers programmed low-intensity
electrical impulses to the nerve 24 hours a day. Clinical-trials data indicate
that over the long term VNS reduces depression symptoms when used in
conjunction with pharmacotherapy.
However, not all patients benefit from VNS, and few seem to achieve
significant acute benefits—a finding that appeared to be a stumbling
block with FDA regulators reviewing Cyberonics' application for approval. The
company did receive an approvable letter for the device in February 2004 and
expects final approval this summer (Psychiatric News, June 17).
Cyberonics declined to comment for this article after issuing a press release
indicating that it had "entered a formal quiet period with regard to all
public communications pending notification by FDA of its final
Because VNS-device implantation requires a surgical procedure,
complications such as wound infection and bleeding can occur. Patients also
have experienced adverse effects from stimulation of the vagus nerve, nearly
as wide-ranging in scope as the nerve's functions in the body. Nausea,
numbness, tingling, and dizziness have been reported.
Deep brain stimulation (DBS) is similar in concept to VNS but involves
implantation of electrodes directly into the brain. Risks of DBS surgery
include intracranial bleeding and stroke, infection, and loss of function.
In the United States DBS is approved only for the treatment of Parkinson's disease, while VNS is approved only for the treatment of epilepsy.
Each of these treatment modalities, Demitrack noted, has helped researchers
further understand the basics underlying the anatomy and physiology of
Foremost, Demitrack said, "We've moved away from looking at
depression in the acute infection paradigm and finally realized that it is
more diabetes-like: it is a chronic, remitting/relapsing disease."
But the real challenge, Demitrack acknowledged, "is to have the
clinical-development activities actually catch up with the advancing
With new technologies, he concluded, "we are forced to bring some
very different threads of evidence [regarding the basis of depression]
together and think differently about what it will take to solve the very
significant treatment gap we currently have." ▪