Statement on Suicidality and Antiepileptic Drugs
On 1/31/08 the Food and Drug Administration published an Alert (http://www.fda.gov/Cder/Drug/InfoSheets/HCP/antiepilepticsHCP.htm) that people taking antiepileptic drugs have "approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%)." The statement was based on analysis of 199 placebo-controlled clinical studies that included nearly 44,000 patients. An advisory committee to the FDA recently agreed that a cautionary statement based on these findings should be included in package information for every antiepileptic drug.
Although the Alert issued by the FDA must be seriously considered by physicians and patients, we believe that additional information is necessary to weigh the overall benefits and risks and antiepileptic drugs. Suicidal thoughts are unfortunately more common in persons with epilepsy. A recent study indicated that up to 13% of patients attending epilepsy clinics have had suicidal thoughts or behavior within the past two weeks. This high base rate of recent suicidality must be considered when determining the clinical relevance of the 0.2% difference reported in the FDA analysis. Also, depression and anxiety occur much more frequently in persons with epilepsy, and are the strongest predictors of suicidal thought and behavior.
In light of the FDA alert and available evidence regarding comorbid psychiatric conditions associated with epilepsy, we suggest the following approach:
A large Danish study provides strong new evidence for an increased risk of suicide among people with epilepsy, raising a cautionary flag for families and clinicians and adding new urgency to research aimed at understanding the reasons why.
Previous studies have uncovered an association between epilepsy and suicide, but their relatively small size has left many questions unanswered. The myriad confounding social and medical factors that influence suicidal tendencies complicate the issue greatly. In particular, it's been difficult to sort out the impact of co-occurring psychiatric disorders, especially depression.
Unraveling this puzzle was a primary goal of the current study, says its principle investigator, Jakob Christensen of Aarhus University Hospital in Denmark. "We know that psychiatric disease is associated with epilepsy. The main issue now is to separate psychiatric disease from epilepsy. For that you need a very large study."
Christensen and his collaborators identified more than 21,000 suicides in Denmark between 1981 and 1997, tracking and comparing incidence of epilepsy and a spectrum of psychiatric disorders with a control group of 423,000 Danish citizens that did not commit suicide. Data on demographic and socioeconomic status was also taken into account.
The results, published in the Lancet Neurology and reported widely in the news media, showed that, overall, people with epilepsy had a three-fold higher risk of suicide compared to people with no history of epilepsy. Unsurprisingly, the risk was highest among people with a history of both psychiatric disease and epilepsy. Yet even after excluding those with psychiatric disease and adjusting for a number of other relevant social factors (e.g., marital and employment status, income, etc.), there was still a doubling of suicide risk among those with epilepsy.
When the investigators examined the timing of suicide, they found a greatly increased risk during the first six months following a diagnosis of epilepsy. The risk waned considerably after one year post-diagnosis.
'Particularly Persuasive' Data
"This is a population-based study that is particularly persuasive and very well done," says Bruce Hermann, a neuropsychologist at the University of Wisconsin who serves as chairman of Epilepsy Foundation's professional advisory board. "I think it certainly adds significantly to previous literature suggesting that the rate of suicide is increased in people who have chronic epilepsy compared to the general population."
Columbia University epidemiologist Dale Hesdorffer, who is also a member of the Epilepsy Foundation's professional advisory board, notes that the Danish results are consistent with her own findings that a history of attempted suicide increases the risk for developing epilepsy. "[The Danish] findings about suicidality after the diagnosis of epilepsy are completely parallel to our findings about suicidality before the diagnosis of epilepsy," Hesdorffer says.
Hesdorffer's team studied a population of Icelandic children and adults newly diagnosed with unprovoked seizures, finding that a history of both major depression and attempted suicide independently increased the risk
for developing seizures. This suggests that depression and attempted suicide may be due to different underlying imbalances in brain chemistry that are each somehow important to the development of epilepsy, she says.
"I think there is a potential for an underlying common vulnerability for both epilepsy and suicidality," Hesdorffer says. "The underlying problem is: What connects these disorders?"
Research to understand the connections is in its infancy, but abnormalities in the brain neurotransmitter serotonin are one target of investigation. Serotonin dysfunction is strongly believed to underlie depression, and the most widely prescribed class of antidepressant drugs, socalled selective serotonin reuptake inhibitors (SSRI's), acts on this system. There is also considerable evidence from animal models of epilepsy to suggest that serotonergic dysfunction lowers the threshold for seizures.
A new study, published in Biological Psychiatryby Kenneth Alper and colleagues at New York University, lends support to the serotonin hypotheses. Capitalizing on Freedom of Information Act regulations that guarantee ccess to public records, the researchers obtained clinical trial data that had been submitted to the FDA as part of pharmaceutical companies' applications to market SSRI's for depression. Such trials, by their nature, include people with strictly defined major depression and exclude people with a history of seizures or any other neurological disease.
Since seizures are one of many adverse events that are tracked in drug trials, Alper's group was able to compare the number of seizures among people taking an SSRI to those in control groups, who took "dummy" placebo pills. They found that the people taking antidepressants had a significantly lower incidence of seizures than those in the placebo group. Moreover, the placebo group's incidence of seizures was dramatically increased relative to the general population.
"This is the best human evidence we have that [seizure development] may have something to do with serotonin," says Hesdorffer. "The people in the placebo group presumably have the same underlying disturbances in brain chemistry as those receiving the SSRI, but they're not getting this extra boost of serotonin, and they're experiencing more seizures.
A Family Issue
Sorting out the many unanswered questions about the interplay of depression with epilepsy and suicide risk – and determining how best to intervene – will take time, given the complexities of the issue. In the meantime, the advice from experts is to be vigilant: learn about the signs of depression and suicide, and seek professional help if you notice any. Vigilance by family and friends is critical.
"Sometimes patients may get accustomed to being depressed, but their family members and loved ones are acutely aware of the depression," says Hermann. "It's now quite easy to check for the presence and severity of depression; it has a certain symptom complex and it responds to treatment. At its worst, it can lead to suicide, so it really needs to be taken seriously."
2011, issue 2-- New Study Narrows Epilepsy Drug Suicide Risk (page 8)
A recent study says the FDA may have overreached when it warned that all antiepileptic drugs can increase the risk of suicidal thoughts and behavior.