MHEI transcript 2 Antiepileptic Drugs and Suicide Risk

PODCAST TRANSCRIPT 2:
ANTIEPILEPTIC DRUGS AND SUICIDE RISK

Neubauer, David N., M.D.
Associate Professor
Psychiatry and Behavioral Sciences
Johns Hopkins Bayview Medical Center

Hello, this is David Neubauer and I would like to welcome you back to this podcast series
focusing on the issues surrounding the suicide risk associated with the use of medications,
particularly antidepressant and antiepileptic agents, and particularly among children,
adolescents, and young adults. This is the 2nd of four podcasts. In the first installment we
reviewed the history of the concern about medications possibly increasing suicidality – meaning
suicidal ideation, as well as suicide attempts and completed suicides. This concern became a
major topic of discussion following the 2004 FDA Black Box warning requirement for
antidepressants prescribed for children and adolescents. In our first podcast we also reviewed
the basis of the FDA warning requirement and the details of C-CASA, the Columbia Classification
Algorithm of Suicide Assessment, which was designed to categorize potential cases of suicidality.

Now, in this second podcast, we will address the topic of antiepileptic drugs (AEDs) and the FDA
actions that did not go so far as a Black Box warning, like with the antidepressants, but did
generate considerable discussion because of the new warnings that were required in the labels
of many of these medications.

The relationship of AEDs and potential suicidality is rather complex, as there are many
dimensions to their possible interactions. Some key questions address baseline suicidality rates
in people treated with these medications, whether any medication-induced suicidality varies
with individual AEDs or specific patient populations – for instance different demographic groups
– perhaps children and adolescents, or people with particular disorders for which AEDs may be
prescribed. We’ll have a closer look at all of these questions, although absolute answers have
not yet been established.

Before turning to the FDA warning regarding AEDs, we should consider the bigger issue of risk of
suicidality and different disorders. Certainly the antiepileptic drugs are prescribed for people
with epilepsy, but some also are widely prescribed for bipolar disorder and chronic pain

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patients, and some AEDs even have approved indications for these disorders. It is no surprise
that bipolar disorder and chronic pain independently are risk factors for suicide. There also is a
long history of reports suggesting that people with epilepsy have a suicide rate greater than the
general population and also have a greater propensity for depressive episodes.

Suicidality in general – particularly suicidal ideation – is very difficult to estimate in any
populations without quite a lot of effort - interviews and well-defined criteria, so most reports
have focused on the somewhat more definable suicide attempts and completions.

Numerous large-scale epidemiologic studies have documented the increased suicide rate among
people with epilepsy. One Danish case-controlled study involving over 21,000 suicides and
found the suicide rate in people with epilepsy to be 3.2 times greater than people without
epilepsy.

Generally speaking, in people diagnosed with epilepsy, the risk for suicidality increases
significantly when there is a comorbid psychiatric disorder. The suicidality risk also is elevated
particularly during the first six months following the epilepsy diagnosis. It is also elevated in
people diagnosed with epilepsy before they are 18 years old, and in people with temporal lobe
epilepsy, and in individuals treated surgically for their epilepsy.

The comorbid psychiatric illness, especially mood disorders, clearly is the strongest risk factor
for suicidality among epilepsy patients. Some authors have speculated that there may be
common underlying mechanisms and that there may be some bidirectionality between epilepsy
and depression or suicidal behaviors. Some evidence suggests that not only are epilepsy patients
at higher risk for depression and suicide, but that people with major depression and suicide
attempts have a greater probability of subsequently developing epilepsy.

Curiously, for a small population of treatment-resistant epilepsy patients, finally achieving a
seizure free state may experience increased suicidality. Perhaps the seizures for these
individuals promote an antidepressant effect analogous to the seizures induced by
electroconvulsive therapy.

So, what about the role of antiepileptic medications and further risk of suicidality and the FDA
actions.

We know that the FDA had examined antidepressant clinical trial data using the C-CASA
classification system and found elevated suicidality in the active medication groups compared



with placebo groups – ultimately leading to the black box warnings for children, adolescents,
and young adults taking antidepressants. By 2005, the FDA was concerned about the possibility
of antiepileptic drugs increasing suicidality risk, so they began plans for an AED meta-analysis.

The FDA employed the same methodology with the AED clinical trial data and in January 2008
issued an alert to healthcare professionals stating that AED groups were associated with nearly
double the suicidality risk compared with the placebo groups. The FDA analysis pooled data
from 199 clinical trials involving 11 different AEDs which were studied as mono- and adjunctive
treatments for epilepsy, psychiatric disorders, and other conditions. Among the nearly 44,000
subjects, 27% were in treatment studies for psychiatric disorders, 25% were in epilepsy
treatment trials, and 48% were in studies for the other possible indications – mostly pain-related
conditions, such as migraine headaches, but also for insomnia, tremor, and obesity. About 63
percent of the subjects were in the active medication groups.

Overall the risk for suicidal behavior or ideation was 0.43% for the active drug subjects and
0.24% for the placebo groups, representing an overall relative risk of 1.8. The FDA reported that
the relative suicidality risk was greatest in the epilepsy treatment trials, but that the absolute
risk was similar in the epilepsy and psychiatric disorder trials. The FDA also reported that the
suicidality risk was generally consistent among all eleven AEDs. The increased suicidality was
noted as early as one week into the clinical trials and continued throughout the trials, which
averaged about 12 weeks. There were 4 completed suicides in the studies and all were in the
AED groups.

The January 2008 FDA alert offered specific recommendations for AED prescribers – no matter
what the indications. Then in July 2008 the FDA convened a public advisory committee meeting
focusing on this issue. The committee recommendation was that the FDA should issue a warning
regarding suicidality, but not require a Black Box warning. The FDA did follow this
recommendation and in December 2008 released a public health advisory regarding the
increased suicidality risk associated with the 11 AEDs and also the details of the required
medication label changes and development of an FDA-approved patient medication guide to
accompany the 11 AEDs whenever they were dispensed.



The eleven AEDs involved in the FDA analysis, and subsequently requiring the suicidality label
warning, were and remain the following:

• Carbamazepine
• Divalproex sodium
• Felbamate
• Gabapentin
• Lamotrigine
• Levetiracetam
• Oxcarbazepine
• Pregabalin
• Tiagabine
• Topiramate
• Zonisamide

As with the previous antidepressant meta-analysis and warning, the antiepileptic meta-analysis
and warning also generated immediate debate that included criticisms of the methodology and
conclusions, as well as the potential clinical implications of the label changes. Again there was a
concern that the warnings would lead prescribers or patients to decrease the use of the
medications, which could lead to a worrisome increase in the seizure risk among epilepsy
patients. It was argued that in epilepsy, the dangers of stopping antiepileptic medications were
much greater than the very small suicide risk.

One of the methodological problems noted was that the FDA excluded all of the trials with no
suicidality reports in either study arm. So, out of the 199 available clinical trials, only 1/3 were
eligible for the main analysis.

Another criticism was that, like with the antidepressants, there was no systematic assessment of
suicidality – the data was dependent on spontaneous adverse event reporting. Accordingly,
there was a potential for reporting bias. The idea is that people on active drugs in clinical trials
are more likely to complain of adverse events.

Other critics argued that it was inappropriate to lump the widely varying AEDs together as a
class and require the identical warning.



Quite a few epidemiologic studies have provided further insights regarding AED use and
suicidality risk.

In a 2010 article in the journal Neurology, Andersohn and colleagues reported the findings of an
observational study based on data from the large United Kingdom General Practice Research
Database. They employed a nested case-control methodology with a population of over 44,000
epilepsy patients treated with AEDs. The patients were categorized according to four AED
classes: Patients taking barbiturates, those prescribed conventional AEDs (phenytoin,
carbamazepine, or valproate), individuals on newer AEDs known to have low depression risk
(lamotrigine, gabapentin, pregabalin, or oxcarbazepine) and patients on the AEDs known to
have higher risks of depression (levetiracetam, tiagabine, topiramate, and vigabatrin). There was
no increased suicidality risk in the first three categories of AEDs. Only the class including the 4
AEDs with the higher depression risk was associated with statistically increased self-harm or
suicidal behavior. When analyzed individually, only levetiracetam was associated with a
significantly elevated self-harm or suicidal behavior risk. Several other studies similarly have
identified the elevated suicidality risk with levetiracetam.

Another very large scale epidemiologic observational study from the UK was published by Arana
and colleagues in the New England Journal of Medicine in 2010. The study database included a
cohort of over 5 million patients and investigated suicide attempts and completed suicides in
people with epilepsy, bipolar disorder, and depression. They did find an increased rate of
suicidal events in people with epilepsy, but treatment with AEDs did not confer greater
statistically significant risk. People with depression who were taking AEDs did have an elevated
suicidal event rate. The authors speculated that the AED use could have been a marker for
greater depression severity accounting for the elevated rate of suicidal behavior. Suicidality
assessed in this study was not increased by AED use in the bipolar disorder patients.

An even larger study reported in Pharmacoepidemiology and Drug Safety by Olesen and
colleagues in 2010 included the entire Danish population over a 10-year period, during which
there were 6,780 completed suicides. The authors found an overall increased risk of suicide with
AED use with an odds ratio of 1.84. Analyzed individually, where there were a sufficient number
of cases, there was an elevated risk of suicide in those taking clonazepam, valproate,
lamotrigine, and phenobarbital, all particularly in the treatment initiation phase.

In yet another 2010 publication, this one in JAMA, Patorno and colleagues, presented a large-
scale database analysis of AEDs and completed suicides, attempted suicides, and violent deaths.



The study population was nearly 300,000 new treatment episodes of AED use. Using topiramate
as a comparator, they found an increased risk of suicidal acts or violent deaths in people
prescribed gabapentin, lamotrigine, oxcarbazepine, and tiagabine.

Has this abundant literature of large-scale epidemiologic studies on suicidality and AED use
answered the questions about whether AEDs actually increases suicidality risk, and if so, are
some of the medications safer than others when it comes to suicide risk? Well, not really. While
there is strength in numbers, there also are methodological limitations regarding diagnoses,
medication compliance, and effective ascertainment of suicidality.

Still, among these many studies, including the clinical trials, there does appear to be a signal of
increased suicidality, at least for some of the AEDs. Unfortunately, very little research has
closely investigated suicidality with specific AEDs.

The FDA based the alert on the increased suicidality identified with the pooled AED data,
although the analyses of individual AEDs demonstrated a non-significant suicidality protective
effect from carbamazepine and divalproex . Considered individually, the only AEDS with
statistically significant suicidality increases were lamotrigine and topiramate, which already had
suicidality risks noted in their labels.

A study by Gibbons and colleagues published in 2010 in Pharmacoepidemiology and Drug Safety,
examined the relationship of gabapentin and suicide attempts. They used a medical claims
database to compare suicide attempt rates one year before and after gabapentin was
prescribed. The cohort studied represented over 130,000 patients with various diagnoses,
including epilepsy, pain disorders, and an assortment of psychiatric disorders. The investigators
found no overall increase in suicide attempts following the introduction of gabapentin, and, in
fact, noted a reduction in suicide attempts in the people with psychiatric disorders.

Redden and colleagues in 2011 published an article in the Annals of General Psychiatry on
divalproex sodium and suicidality. Similar to the FDA AED analysis, this was a meta-analysis of
clinical trials including the C-CASA methodology to determine suicidality. The authors concluded
that there did not appear to be an increase in suicide-related adverse events with divalproex
relative to placebo.

A few studies have examined suicidality with AEDs in populations of patient with specific
disorders. The majority have been with epilepsy. In a 2012 publication by Leon and colleagues in
the American Journal of Psychiatry, the authors specifically investigated three AEDS approved



for treating bipolar disorder – carbamazepine, lamotrigine, and valproate in relation to suicide
attempts and suicides. During a 30-year follow up period, the bipolar patients did not have an
increase in suicide attempts or suicides when exposed to AEDs compared to when they were not
taking them.

What about age and suicidality and AED use? Recall that the FDA antidepressant Black Box
warning refers to increased suicidality in children, adolescents, and young adults. However,
further down in the Warning section of the prescribing information, it is noted that
antidepressant use may be associated with increased suicidality in both pediatric and adult
populations. The AED suicidality warning does not suggest an elevated risk at any particular age.
In fact, the required label wording for AEDs notes that the suicidality risk varied little with ages
the pooled analysis, which included an age range of 5 to 100 years.

What’s the bottom line? There may be a small increased risk of suicidal thinking and suicide
attempts and completed suicides, although with some AEDs appear to be associated with
greater risk while others may be somewhat protective.

So, like the AED labels state, educate patients about the suicidality risk and monitor them for
symptoms of suicidality while they are taking these medications.

We’ll look more closely at strategies to monitor patients for suicidality in the future podcasts in
this series.

Thank you for joining us today.



MHEI transcript 2 Antiepileptic Drugs and Suicide Risk

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MHEI transcript 2 Antiepileptic Drugs and Suicide Risk