Suicidality and Antiepileptic Drugs

22 june 2008--Data from 199 placebo-controlled clinical studies covering eleven different antiepileptic drugs were reviewed and analyzed for reports of suicidal behavior (completed suicides, suicide attempts and preparatory acts) and suicidal ideation. The studies examined the effectiveness of the drugs in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression and anxiety) and other conditions (e.g., migraine and neuropathic pain syndromes). The analysis included a total of 43,892 patients ages five and older (27,863 in drug treatment groups and 16,029 in placebo groups).
There was a statistically significant increased risk of suicidal behavior and suicidal ideation in the patients randomized to receive an antiepileptic drug compared to patients who received a placebo. The estimated overall risk was about twice that of the placebo group. There were an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation than in the placebo groups.
Four of the patients who were taking one of the antiepileptic drugs committed suicide, whereas none of the patients in the placebo group did. The increased risk of suicidal behavior and suicidal ideation was observed at one week after starting the drug and continued to at least 24 weeks. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be reliably assessed.
FDA will be working with manufacturers of marketed antiepileptic drugs to include this new information in the labeling for these products. FDA is also planning to discuss these data at an upcoming advisory committee meeting.
All patients treated with antiepileptic drugs should be monitored for suicidality and other unusual changes in behavior. Symptoms such as anxiety, agitation, hostility, mania and hypomania may be precursors to emerging suicidality.
Healthcare professionals who prescribe antiepileptic drugs should:
Balance the risk for suicidality with the clinical need for the drug
Be aware of the possibility of the emergence or worsening of depression, suicidality, or any unusual changes in behavior;
Inform patients, their families, and caregivers of the potential for an increase in the risk of suicidality so they are aware and able to notify their healthcare provider of any unusual behavioral changes.
Information for patients, family members, and caregivers:
Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
Talking or thinking about wanting to hurt yourself or end your life
Withdrawing from friends and family
Becoming depressed or having your depression get worse
Becoming preoccupied with death and dying
Giving away prized possessions
If these or any new and worrisome behaviors occur, contact the responsible healthcare professional immediately.
Background and Data Summary
After preliminary analyses of data from several drugs in this class suggested an increased risk of suicidality, in March 2005, FDA requested data from manufacturers of marketed antiepileptic drugs for which there were adequately designed controlled clinical trials in order to review the possible association between these drugs and suicidality events. In an effort to obtain the most complete and accurate data for this review, requests for additional information and clarification were sent to the manufacturers in 2006 and 2007. The analyses performed were similar to those performed by FDA for antidepressant drugs in the last several years.
One-hundred ninety nine placebo-controlled clinical studies covering eleven different drugs were included in the primary analysis. The conditions studied in these clinical trials included epilepsy, selected psychiatric illnesses, and other indications, including migraine and neuropathic pain syndromes. The analysis included 27,863 patients in drug treatment groups and 16,029 patients in placebo groups. Patients included in the analysis were five years of age or older. The individual sponsors of the drugs were responsible for identifying suicidal behavior and suicidal ideation events in their databases based on the instructions provided by FDA.
There were 4 completed suicides among patients in drug treatment groups and none among the patients in placebo groups. Overall, 0.43% of the patients in drug treatment groups experienced suicidal behavior or ideation versus 0.22% of the patients in placebo groups, corresponding to an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation than in the placebo treatment groups (See Table). In this analysis, the relative risk for suicidal thoughts or behavior was higher for patients with epilepsy compared to those patients with psychiatric or other disorders (See Table). The higher risk for suicidal behavior or suicidal ideation was observed at one week after starting a drug and continued to at least 24 weeks. The results were generally consistent among the drugs and were seen in all demographic subgroups. Specifically, there was no clear pattern of risk across age groups.

Hormonal Effects of Antiepileptic Drugs are Reversible

LORENSKOG, Norway, Oct. 26 -- Common antiepileptic drugs can negatively affect reproductive endocrine function, but the changes may be reversible even after years of chronic use, investigators here reported.
In a randomized double-blind study, both men and women who were withdrawn from carbamazepine, for example, had significant increases in serum testosterone and free androgen index compared with patients who stayed on the drug, reported Morten Lossius, M.D., of Akershus University Hospital and the National Center for Epilepsy, and colleagues.
"The increase in the free androgen index found in the present study shows that the decrease in free androgen index associated with carbamazepine treatment is reversible," the authors wrote in the October issue of Epilepsia.
The study evaluated the effects of antiepileptic drug withdrawal on reproductive endocrine function -- specifically, whether the known suppressive effects of the drugs on endocrine function could be partially or fully reversible.
The investigators studied 70 men and 80 women from the ages of 18 to 67 who had epilepsy (defined as at least two unprovoked seizures) and who had been seizure-free for at least two years while on antiepileptic drug monotherapy.
The patients were randomly assigned to drug withdrawal via dose reduction and placebo substitution, or no withdrawal.
Blood samples were taken and evaluated at baseline and at four months after the time of complete withdrawal (or no withdrawal) for total testosterone, 17-beta-estradiol, progesterone, sex hormone binding globulin, follicle stimulating hormone, luteinizing hormone, free androgen index, insulin, estradiol/sex hormone binding globulin ratio and C-peptide.
Complete before-and-after serum samples for 130 patients were available for analysis at the end of the one-year study.
"The main finding was that reversible endocrine changes in sex steroid hormone levels could be observed in both sexes after withdrawal of antiepileptic drugs," the authors wrote.
Patients assigned to carbamazepine withdrawal had significant increases in serum testosterone concentrations (P=0.001) and free androgen index in both men and women (19 in each group).
Mean differences in change in the free androgen index between the withdrawal group and nonwithdrawal group were 17.49 (95% confidence interval, 10.16 to 24.81, P ≤ 0.001) in men, and 1.61 (95% CI, 0.62-2.61, P ≤ 0.001) in women.
"Our findings provide further evidence of the potentially negative effects of carbamazepine treatment on reproductive endocrine functions in men and women, but also show that some of these changes may be reversible, even after years on treatment," the authors wrote.
The numbers of both men and women on valproic acid (Depakene, Depakote) were too small to draw statistically significant conclusions about the effects of withdrawal on endocrine levels, they noted.
Neither the study funding source nor author conflicts of interest were listed. Primary source: EpilepsiaSource reference: Lossius MI, et al "Reversible Effects of Antiepileptic Drugs on Reproductive Endocrine Function in Men and Women with Epilepsy-A Prospective Randomized Double-blind Withdrawal Study." Epilepsia 48; 10: 1875-1882.