Experts in neurology and psychiatry agreed with the Food and Drug
Administration's (FDA) assertion that antiepileptic drugs, as a class,
increase the risk of suicidal thoughts and behaviors, but they were concerned
about the negative consequences of imposing a black-box warning on the
At a joint meeting on July 10, members of the peripheral and central
nervous system and psychopharmacology advisory committees voted in favor of
adding warnings and precautions about the suicidality risk to the package
inserts of all antiepileptic drugs—but not in the form of a black-box
In 2005, the agency began asking the makers of 11 drugs approved for
long-term treatment of epilepsy to submit data on the drugs and
suicide-related events reported in randomized, parallel-arm,
placebo-controlled trials the companies conducted. Earlier this year, the FDA
announced the results of its preliminary analysis and warned about a suspected
increase in suicidality risk in patients taking antiepileptics
(Psychiatric News, March 7).
The 11 drugs included in the analysis were carbamazepine, divalproex
sodium, felbamate, gapapentin, lamotrigine, levetiracetam, oxcarbazepine,
pregabalin, tiagabine, topiramate, and zonisamide. Many other drugs that carry
the indication for treating epilepsy were not included because they are sold
in generic formulations by multiple manufacturers, which have little incentive
to conduct clinical trials. Also, the original clinical trial data for these
drugs may be too old, nonrandomized, without placebo control, or difficult to
Suicidality was defined as completed suicide, attempted suicide,
preparatory acts toward imminent suicidal behavior, or suicidal ideation.
At this meeting, FDA staff presented updated analyses based on pooled data
from 199 clinical trials involving 27,863 patients on active drugs and 16,029
on placebo. The prevalence of any suicidality event was 0.22 percent in
patients on placebo and 0.37 percent in those on active drugs. The odds ratio
between them was 1.80. The difference between placebo and antiepileptics was
statistically significant. The pooled trial data encompassed various
indications such as epilepsy, psychiatric disorders, and pain.
Based on the statistical analyses, this risk difference is equivalent to an
increase of 1.9 patients with suicidality in every 1,000 patients taking
antiepileptic drugs compared with those on placebo.
The FDA had enough data for analysis up to 24 weeks, and the risk of
suicidality appears to persist throughout this period. The risk difference
between placebo and active drugs is unknown between patients with epilepsy and
bipolar disorder who may take the drugs for years.
At the advisory committees' meeting, Pfizer representatives vehemently
argued that its two drugs, pregabalin and gabapentin, were different from the
other antiepileptics in the analyses and should be exempt from carrying the
suicidality warning. These two drugs, however, were not the least risky of the
11 drugs analyzed. Carbamazepine and divalproex had odds ratios below 1 in the
analyses, meaning that the risk of suicidality associated with these drugs was
lower than for placebo in clinical trials of these two drugs. In addition, the
individual risk with felbamate could not be calculated because no suicidal
behavior or ideation was reported in its trials.
Nevertheless, the FDA position is that this "signal" of
increased suicidality is a class effect, even though these 11 antiepileptic
drugs have different direct biological effects on the nervous system. Mark
Levenson, Ph.D., the FDA reviewer who conducted the analyses, pointed out that
felbamate and carbamazepine had the two smallest datasets among the 11 drugs
(both under 1,000 patients), and the low risk observed may be a result of the
small sample size.
While 20 of the 21 members of the advisory committees concurred with the
FDA analyses and the conclusion about an elevated suicidality risk, 18 members
voted "yes" to the question of whether the increased risk should
be applied to all 11 antiepileptic drugs; three members voted"
The agency then asked the advisory committees whether they believed this
suicidality risk should be extrapolated to all drugs approved for treating
epilepsy, even though there are no randomized, placebo-controlled clinical
data for direct analyses except for these 11 drugs.
With a 15-5 vote and one abstention, the committees agreed with the
agency's recommendation, showing a growing unease with expanding the
conclusion to other drugs without direct evidence to support it. This vote
was, in part, driven by the worry that some clinicians may be inclined to
prescribe older antiepileptics if a suicidality warning was imposed on only
newer drugs, even though there is no evidence that the older drugs are
To further complicate the debate, many of the drugs in this class are
prescribed for a variety of indications. Carbamazepine and lamotrigene, for
example, are major treatments for bipolar disorder. Pregabalin is approved for
neuropathic pain, and topiramate for migraine. Off-label use is common among
these drugs. The risk-benefit ratio can differ dramatically depending on the
illness for which the drugs are used.
"We are concerned about the clinical impact of reduced use of mood
stabilizers," said Darrel Regier, M.D., M.P.H., director of the American
Psychiatric Institute for Research and Education, in his testimony to the
advisory committees and the FDA. He urged the agency to refrain from requiring
the black-box warning and pointed to the substantial risk of suicide if
bipolar patients go without adequate treatment.
"The data in the FDA analyses do not seem to suggest that the rate of
suicidal thoughts and behaviors [linked to antiepileptics] outweighs the
potential harm from possible medication discontinuation as a result of a
black-box warning," he said.
Laurence Greenhill, M.D., president of the American Academy of Child and
Adolescent Psychiatry, echoed Regier's concerns in his testimony. "As we
have learned from previous experience, the FDA's decision to use a black-box
warning significantly influenced prescribing in psychiatry and impacted
patient care." Patients with serious neurological and psychiatric
disorders could face life-threatening risks if they choose to stop taking
these necessary treatments out of fear linked to the black-box warning, he
"There is a need for prospective, systematic analysis of suicidality
as opposed to relying on retrospective, spontaneous reports of suicidal events
in clinical trials," regier said.
Many members on the advisory committees expressed concerns about the
unintended consequences of black-box warnings on patient care. The documented
reduction in antidepressant prescribing in pediatric and adult patients with
depression after the black-box warning about suicidality was issued in 2004,
and the warning's impact on public health, continues to worry some
In the end, the advisory committees voted 14-4, with three abstentions, to
recommend against imposing a black-box warning for all antiepileptic
The FDA faces a difficult decision because it has limited means to
communicate nuanced risk information to the public and clinicians. Russell
Katz, M.D., director of the agency's Division of Neurology Products, told
reporters after the meeting that the final decision on the warning for
antiepileptic drugs will be announced soon. In the past, the FDA has
frequently, but not always, followed the recommendations of its advisory