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1.4. Safety Considerations Specific to
Depressed Patients
Two specific safety concerns in the use of all antidepressant therapies are
the precipitation of manic or hypomanic episodes and the possible effect of
antidepressant therapy on suicidal ideation and behavior.

1.4.1. Antidepressant treatments and manic or
hypomanic reaction
Although patients with bipolar disorder experience manic episodes as the
cardinal feature of their disorder, effective antidepressant therapies
themselves can occasionally precipitate a manic or hypomanic episode.
Antidepressant therapies can also occasionally precipitate a manic or
hypomanic episode in patients without a prior history of mania who are
being treated for a major depressive episode.

1.4.1.1. Manic reactions
In the pivotal (D-02) study, six hypomanic or manic reactions were
identified according to DSM IV criteria or the Young Mania Rating Scale
(YMRS). Five were observed in subjects with a known history of prior
hypomanic or manic episodes. One of the events was considered serious
and the subject was hospitalized.

1.4.2. Suicidal ideation, suicide attempts, suicide, and
worsened depression
Suicidal ideation was analyzed by examining the HRSD24 Item 3 scores.
At 12 months of VNS Therapy, 90% of the subjects in the pivotal (D-02)
study showed either improvement (56%) or no change (34%) in their Item
3 scores. During the acute D-02 study, 2.6% of the sham subjects and 1.7%
of the stimulation subjects increased their Item 3 score by 2 or more
points, indicative of an increase in suicidal ideation. During the long-term
D-02 phase, 2.8% of the subjects had an increase in their Item 3 score by at
least 2 points at 12 months compared to baseline. In a non-randomized
control group of subjects treated with standard antidepressant therapies
without VNS Therapy (the D-04 study population), 1.9% of the subjects
had an increase of at least 2 points. Based on the occurrence of any
increase in Item 3 score from baseline to 12 months, 10% of the D-02
subjects had an increase compared to 11% of the D-04 population.
Conversely, 27% of the D-02 subjects decreased their score by at least 2
points at 12 months compared to baseline, whereas only 9% of the D-04
subjects did.

Suicide attempts and completed suicides in the D-02 and D-04 studies are
shown in Table 3. As noted above, one subject committed suicide in the
acute phase and six attempted suicide during the long-term phase of the D-
02 study (N = 235). One of the six subjects noted in the long-term phase
attempted suicide twice. Although safety data were not prospectively
collected for the D-04 study, the health care utilization form documented
suicide attempts. Three suicide attempts were reported for the D-04 study
through the first year of the study (N=124).





3. GUIDELINES FOR PATIENT FOLLOW-UP____
During the first few weeks after implantation, the patient should be seen to
confirm wound healing and proper Pulse Generator operation. The Pulse
Generator’s output current for both the magnet and the programmed
stimulation must be 0.0 mA for the first 14 days after implantation.
The VNS Therapy System is an adjunctive therapy to existing (prior to
device implantation) antidepressant medications. Cyberonics strongly
encourages physicians to keep all antidepressant medications stable for
the first three months of stimulation before attempting to reduce or
change a patient’s medication.

During initial programming, the output current should be programmed to
start at nominal parameters (0 mA) and then be slowly increased in 0.25
mA increments until the patient feels the stimulation at a comfortable
level. Patients who are receiving replacement generators should also be
started at nominal parameters, with 0.25 mA-step increases to allow reaccommodation.

At each patient visit, the Pulse Generator should be interrogated, using the
appropriate version of the VNS Therapy Programming Software. After
reprogramming and/or diagnostics testing, data should be printed out and
filed. These data can be used for comparison with a patient’s diary or own
records to evaluate the VNS Therapy System, to confirm proper VNS
Therapy System functioning, and to assess the need for reprogramming.
The median output current used during the clinical studies was about 1.0
mA. Other standard treatment settings were 20 Hz, 500 ìsec pulse width,
30 sec ON time, and five min OFF time. There are no data to verify that
these are optimal parameters.

There is no proven correlation at present between high output current
(mAmps) and device effectiveness, nor is there a standard treatment level
that needs to be achieved during treatment ramping. VNS Therapy System
treatment should not be uncomfortable, nor should it cause bothersome
side effects. Patients should be observed for at least 30 minutes after the
last stimulation adjustment to make certain that they are comfortable with
both magnet-activated and programmed stimulation.

Although Cyberonics recommends adjusting output current as necessary,
there are no controlled data at this time to indicate that higher current
levels are associated with better efficacy. Patients whose seizures are well
controlled at follow up should not have their settings changed unless they
experience uncomfortable side effects.

The subsequent follow-up schedule and the nature of each examination
should be determined by the physician on the basis of patient response to
and tolerance of the implant. In all other respects, follow up should be
performed in accordance with the standard medical practice for patients
with depression.

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