VNS (vagus nerve
stimulation) Therapy
VNS (vagus nerve stimulation) Therapy

What is VNS Therapy?
· VNS (vagus nerve stimulation) Therapy consists of an implanted pacemaker-like device
that delivers mild, intermittently pulsed signals to the patientÂ’s left vagus nerve, which
then activates various areas of the brain.

· Roughly the size of a small pocket-watch and weighing less than one ounce, the device
is implanted in the patientÂ’s left chest area. A thin thread-like wire, attached to the
generator, runs under the skin to the left vagus nerve in the neck.

· The implant procedure typically takes approximately one to two hours.

· Although the VNS Therapy surgical procedure does not involve the brain, stimulation of
the left vagus nerve has been shown to induce widespread bilateral effects in areas of the
brain implicated in seizures and mood disorders and responsible for modulation of key
neurotransmitters such as serotonin and norepinephrine.

· Using an external dose adjustment system, physicians can adjust the stimulation
duration, frequency and intensity.

Indications for VNS Therapy

VNS (vagus nerve stimulation) Therapy is FDA approved as an adjunctive, long-term
treatment for chronic or recurrent depression for patients 18 year of age or older who are
experiencing a major depressive episode and have not had an adequate response to four
or more adequate antidepressant treatments.

VNS Therapy was previously approved in the U.S. in 1997 as an adjunctive therapy for
reducing the frequency of seizures in adults and adolescents over 12 years of age with
partial-onset seizures which are refractory to antiepileptic medications.

VNS Therapy is currently approved for sale as a treatment for epilepsy in all the member
countries of the European Union, Canada, Australia and other markets. VNS Therapy
System is also approved for sale in the European Union (March 2001) and in Canada
(April 2001) as a treatment for depression in patients with treatment-resistant or treatment
intolerant major depressive episodes including unipolar depression and bipolar disorder
(manic depression).

VNS Therapy will soon be available in many major cities. It will be available first in cities
where the clinical studies were conducted including Dallas, Houston, Charleston, San
Francisco, Chicago, and New York among others.

VNS Therapy is at various levels of investigational clinical studies as a potential treatment
for anxiety disorders, AlzheimerÂ’s disease, bulimia and chronic headache/migraine.

VNS Therapy Clinical Studies in Depression

In 2003 and 2004, clinical studies were concluded in the United Sates to support the
approval of VNS Therapy for the adjunctive long-term treatment of chronic and recurrent
depression. Results from these studies were incorporated into a PMA-Supplement
application submitted to the FDA for approval on October 27, 2003. An amendment to this
submission was made in September 2004 with additional long-term data.

For many patients, VNS Therapy offers significant improvements in physical, mental and
emotional well-being, vitality and social interaction.1

Clinical study results indicate VNS Therapy has the potential to provide relief to those with
longstanding depression which has not responded to other antidepressant therapies.2
Study results also show that patients who use VNS Therapy may continue to show clinical
improvement in both their depression symptoms and quality of life over time.3

Results from clinical trials indicate that VNS Therapy is not associated with sexual
dysfunction or memory impairment. Animal studies also reveal no evidence of impaired
fertility or harm to the fetus due to VNS Therapy. Sleep disturbance and weight gain
(commonly reported with other antidepressant treatments) have been reported by less
than two percent of patients receiving VNS Therapy.

Because VNS Therapy is not a drug, it produces no drug interactions with concurrent
antidepressant medications.

VNS Therapy Experience in Epilepsy

To date, more than 30,000 patients worldwide have accumulated over 79,000 patient
years of experience using VNS Therapy.

The implant procedure does not involve the brain and is a short outpatient procedure.
There is a very low incidence rate of minor complications.

VNS Therapy has been proven to effectively decrease seizures.4 Many physicians and
patients report that the quality of life is improved by the reduction in frequency and
severity of seizures.5

VNS Therapy provides seizure reduction and quality-of-life benefits that improve over time.
6

Common Side Effects with VNS Therapy

The common side effects associated with VNS Therapy include hoarseness, sore throat,
shortness of breath and coughing.7

Side effects typically occur only during stimulation and typically diminish over time.8



Frequent Ask Questions

Is VNS Therapy for depression currently available to treat people with depression?
Yes, the FDA has now approved VNS Therapy as an adjunctive (add-on), long-term
treatment for chronic or recurrent depression for patients 18 years of age or older who
are experiencing a major depressive episode and have not had an adequate response to
four or more adequate antidepressant treatments. VNS Therapy is also approved for use
in Europe and Canada for depression in patients with treatment-resistant or treatment
intolerant major depressive episodes including unipolar depression and bipolar disorder
(manic depression).
Why was VNS Therapy studied for patients with chronic or recurrent treatment-resistant
depression?
VNS Therapy received FDA approval in 1997 for the treatment of adults and adolescents
over 12 years of age with partial onset seizures that are refractory to antiepileptic
medications. To date, more than 30,000 patients have been treated with VNS Therapy.
The suggested link between VNS Therapy and potential antidepressant efficacy lies
primarily in the fact that many of the patients with epilepsy who were treated with VNS
Therapy reported improved mood. Subsequent clinical studies demonstrated that patients
with epilepsy experienced significantly improved mood when treated with VNS Therapy,
and these mood improvements occurred irrespective of seizure control. Additionally, some
anticonvulsant medications have been shown to have antidepressant or mood stabilizing
efficacy.
Although the VNS Therapy surgical procedure does not involve the brain, stimulation of
the left vagus nerve has been shown to induce widespread bilateral effects in areas of the
brain implicated in seizures and mood disorders and responsible for modulation of key
neurotransmitters such as serotonin and norepinephrine.
VNS Therapy offers a unique safety profile. To date, more than 30,000 patients with
epilepsy worldwide have accumulated over 79,000 patient years of experience using VNS
Therapy as an approved anticonvulsant treatment. VNS Therapy also provides assured
patient adherence. VNS Therapy is very well tolerated and there are no drug interactions
with VNS Therapy and concurrent antidepressant medication.

What studies have been conducted to determine VNS TherapyÂ’s efficacy in treating
depression?

CyberonicsÂ’ VNS Therapy depression study program began with the first pilot study
implant in July 1998. The depression study program includes the following studies: a 60-
patient acute and long-term pilot study (D-01); a 235-patient double blind, randomized,
placebo controlled 8-week fixed dose acute pivotal study with an open label long-term
extension (D-02); a 127-patient long-term observational study of patients with chronic or
recurrent treatment-resistant depression treated only with treatment as usual (D-04);
neuroimaging, neurochemical and sleep mechanism of action studies; and several
healthcare utilization and cost effectiveness studies. The patients in these studies were
experiencing chronic or recurrent treatment-resistant depression. In the D-02 and D-04
studies, the average lifetime illness exceeded 25 years and the average duration of the
current depressive episode exceeded 48 months.
In January 2002, Cyberonics announced that the difference in the D-02 treatment and
placebo group in the 24-item Hamilton Rating Scale (HAM-D) response rates at the end of
the eight-week fixed dose acute study was clinically meaningful, but not statistically
significant. In September 2002, Cyberonics submitted a revised, prospective long-term
pivotal study analysis plan to the FDA. That plan was designed to determine the statistical
and clinical significance of the long-term improvements from baseline in all D-02 study
patients treated over a one-year period with adjunctive VNS Therapy and treatment as
usual. Additionally, the study would compare D-02 outcomes with the outcomes of the D-
04 patients who were treated only with treatment as usual.

What do the studies demonstrate about VNS Therapy for depression?

Clinical study results demonstrate that VNS Therapy is effective in treating chronic or
recurrent treatment-resistant depression, and that patients with depression who respond
to treatment with VNS Therapy are likely to maintain their improvement.19 In the 12-month
follow-up of D-02 patients, 30 percent of patients with chronic or recurrent depression
responded to VNS Therapy compared to 13 percent of D-04 patients receiving medication
only, but no VNS Therapy. Seventeen percent of patients treated with VNS Therapy
achieved remission,20 compared to seven percent of patients receiving medication only,
but no VNS Therapy.21 Patients with depression who achieve remission no longer meet
the criteria for major depression. Overall, it has been shown that VNS Therapy may
improve the quality of life of patients who have been treated for depression.22
When should VNS Therapy for treatment-resistant depression be considered?
VNS Therapy for treatment-resistant depression has been indicated as an adjunctive long-
term treatment for patients 18 years or older with chronic or recurrent depression who are
experiencing a major depressive episode and have not had an adequate response to four
or more adequate antidepressant treatments.

How does VNS Therapy work?

VNS Therapy is delivered via a small pacemaker-like device that is implanted just under
the skin during a short, outpatient procedure that does not involve the brain. The device is
implanted in the left chest area. A thin flexible wire connects the device to the left vagus
nerve in the neck. Once activated by the physician, the device sends precisely timed and
measured mild pulses to the left vagus nerve. The stimulation dose is adjusted via an
external telemetric wand and special software to stimulate the vagus nerve at regular
intervals, 24 hours a day. Using this dose adjustment system, physicians can adjust the
timing and amount of the stimulation the patient receives. There is an extensive body of
data demonstrating the association between vagus nerve stimulation and brain activation.
Brain imaging studies have demonstrated that VNS Therapy modulates blood flow and/or
metabolism in many areas of the brain that are affected in mood disorders.

What are the side effects of VNS Therapy?

Side effects associated with VNS Therapy are mild to moderate, typically stimulation
related and typically decrease over time. The most commonly reported side effects during
the depression clinical studies were hoarseness, paresthesia (an abnormal sensation
such as tingling), dysphagia (difficulty swallowing) and dyspnea (shortness of breath).23

How much will VNS Therapy cost?

The cost of VNS Therapy for the treatment of epilepsy is approximately $20,000 to
$25,000 initially. Hospital charges vary, so the cost can differ. In epilepsy, most third party
payors reimburse for the procedure, as well as Medicare and Medicaid in most states. It is
anticipated that the experience in depression may be similar over time. The dose settings
impact how long the battery will last. For example, the battery may last 3 years at a higher
setting, compared with 8 years at a lower setting.

Where will VNS Therapy be available?

VNS Therapy will soon be available in most major cities. It will be available first in cities
where the clinical studies were conducted including Dallas, Houston, Charleston, San
Francisco, Chicago and New York among others.
How can patients learn more information about VNS Therapy for treating depression?

Knowledgement
Cyberonics Inc. provide most of the information for this article. For more information about
VNS Therapy, patients can call 1-877-NOW-4-VNS or visit
www.VNSTherapy.com.

To learn more about health issues or supplements, visit
zhion.com.
To learn about depression, visit
depression.
To read corporate fact sheet about Cyberonic Inc., visit
Cyberonic.

REFERENCES
1 Marangell L., Rush AJ, George M, et al. “Vagus Nerve Stimulation (VNS) for Major
Depressive
Episodes: One Year Outcomes.” Biological Psychiatry; 2002. (51)4:284, 285–86.

2  Rush AJ, George M, Sackeim HA, Marangell L, et al. “Vagus Nerve Stimulation (VNS)
for Treatment-Resistant Depressions: A Multicenter Study.” Biological Psychiatry; 2000.
(47);4:276-286.

3 Marangell L., Rush AJ, George M, et al. “Vagus Nerve Stimulation (VNS) for Major
Depressive
Episodes: One Year Outcomes.” Biological Psychiatry; 2002. (51)4:284, 285–86.

4 Kaakaji W, Geller EB, Bingaman WE. “Vagal Nerve Stimulation for the Treatment of
Refractory
Seizures: A Preliminary Experience.” Poster #1360 Presented at the 1999 American
Association of
Neurological Surgeons Meeting.

5 Tatum WO, Johnson KD, Goff S, et al. “Vagus nerve stimuation and drug reduction.”
Neurology; 2001.
(56)4:562.

6 Morris G, Mueller W. “Long-term treatment with vagus nerve stimulation in patients with
refractory
epilepsy.” Neurology; 1999. (53)7:1733–34.

7 “Physician’s Manual: VNS Therapy Pulse Model 102 Generator.” Houston, TX:
Cyberonics, Inc; 2003.

8 “Patient’s Manual for Vagus Nerve Stimulation with the NeuroCybernetic Prosthesis
(NCP®) System,”
Produced by Cyberonics, October 2000.

19 Marangell L, Rush JA, George MS, et al. “Vagus Nerve Stimulation (VNS) for Major
Depressive Episodes: One Year Outcomes,” Biological Psychiatry, 2002; 51 (4) 280 - 287

20 Rush AJ, George M, Sackeim HA, Marangell L, et al. “A One-Year Longitudinal Study
of VNS Therapy in Patients with Treatment-Resistant Depression,” Presented at the
42nd American College of Neuropsychopharmacology Annual Meeting

21 Cyberonics Depression PMA Supplement (PMA-S) to the U.S. Food and Drug
Administration (FDA). Produced by Cyberonics, October 2003.

22Sackheim HA, Rush JA, George MS, et al. “Vagus Nerve Stimulation for Treatment-
Resistant Depression: Efficacy, Side Effects and Predictors of Outcome,” Journal of
Neuropsychopharmacology. 2001; (25):5:713-728.

23 Marangell L, Rush JA, George MS, et al. “Vagus Nerve Stimulation (VNS) for Major
Depressive Episodes: One Year Outcomes,” Biological Psychiatry, 2002; 51 (4) 280 –
287.

                                   
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