FDA Warnings About Suicidality: Balancing Risk and Benefit

A new FDA policy requires pharmaceutical manufacturers to examine whether study participants become suicidal during clinical trials of new medications.¹ The policy derives from the belated recognition that antidepressants seem to slightly increase suicidality in children, adolescents, and young adults early in the course of treatment. This is not the only news about medications linked to possible increases in suicidal ideation or behavior.

Antiseizure Medications

On January 31, the FDA issued a warning on its Web site specifically about antiseizure medications. Like antidepressants, these drugs are associated with an increased risk of suicidality. An FDA analysis of 27,863 persons receiving antiseizure medications in 199 placebo-controlled clinical studies of 11 drugs revealed 4 completed suicides among persons given the medication compared with no completed suicides among those given placebo (16,029 persons).² The drugs included in the analysis were carbamazepine (Carbatrol, Equetro, Tegretol, Tegretol XR), felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), pregabalin (Lyrica), tiagabine (Gabitril), topiramate (Topamax), valproate (Depacon, Depakene, Depakote, Depakote ER), and zonisamide (Zonegran).

Overall, 0.43% of the participants in the drug treatment groups experienced suicidal behavior or ideation versus 0.22% of those in the placebo groups. According to the FDA, the relative risk of suicidal thoughts or behavior was higher in persons with epilepsy than in persons with psychiatric or other disorders (eg, migraine, neuropathic pain syndromes). The higher risk of suicidal behavior or suicidal ideation was observed at 1 week after therapy initiation and continued for at least 24 weeks (when most studies ended).

Unlike with antidepressants, use of antiseizure medications did not show a clear pattern of risk across age groups. Specifically, younger participants were at no higher risk than older participants (children younger than 5 years were not included in the placebo-controlled trials).

Although the FDA has not yet said it will require black box warnings for antiseizure medications, the agency is advising health care professionals who prescribe these medications to do the following:

• Balance the risk of 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 health care provider of any unusual behavioral changes.²

While the FDA is correct in warning health care professionals and the public about the connection between antiseizure drugs and a possible increase in suicidality, there is no guarantee that such action will result in improved health. In fact, there is a risk that the warnings will backfire and produce an immediate precipitous decline in prescriptions for antiseizure medications. Consider the evolving story of what has recently transpired following the warnings of the association of a possible increase in suicidality and antidepressants.

Suicide Risk and Antidepressant Medications

In October 2003, the FDA issued a public health advisory citing reports of a potential increased risk of attempted or completed suicide in children and adolescents taking antidepressants. One year later, the FDA ordered pharmaceutical manufacturers to add a black box warning to the labeling of all antidepressants based on data from randomized controlled trials suggesting a 2-fold increase in suicidal ideation and behavior when antidepressants, including SSRIs, were prescribed for youths who were not actively suicidal.

Even before the black box warning on antidepressants, the increased awareness of a possible increase in suicidality (early in the course of treatment) resulted in a dramatic decrease in the number of persons younger than 18 years filling antidepressant prescriptions. Data from Medco Health Solutions showed that the number of persons younger than 18 years receiving antidepressants decreased by 18% between the end of the last quarter of 2003 and the end of the first quarter of 2004, and that this figure continued to decline in the second quarter of 2004, with an additional 5% drop.³ This decline contrasts sharply with a 77% increase in prescription drug spending for antidepressants and other psychotropic medications for children and adolescents between 2000 and 2003.

According to CDC data, among children and adolescents, 1737 suicides were recorded in 2003 in a population of 61,447,723 (2.83 per 100,000 persons) and 1985 suicides were recorded in 2004 in a population of 61,469,792 (3.23 per 100,000), for a 14% increase in the suicide rate between 2003 and 2004 (P < .0001). Data from the Netherlands for the 2003-2005 period-that is, before and after the European authorities issued warnings-indicated that the SSRI prescription rate declined by approximately 22% for persons younger than 20 years, and the overall suicide rate increased by 49% in this age group.⁴

These increases in the suicide rate coincided with a decline in antidepressant prescription rates in both the United States and the Netherlands. This is especially noteworthy given the previous trend. From 1998 to 2003, SSRI prescription rates increased substantially, while suicide rates declined. In the United States, antidepressant prescription rates increased by 91%, whereas suicide rates decreased by 33%; in the Netherlands, a 120% increase in prescription rates accompanied a 31% decrease in the suicide rate.⁴

FDA Recommendation Not Followed

The FDA warnings about the possible increased risk of suicidality in children and adults who received antidepressants emphasized "close supervision" by health care providers rather than limiting antidepressant prescriptions. Contrary to expectations, the frequency of provider contacts for persons with new depressive episodes given antidepressants did not increase after the October 2003 FDA advisory was issued. Rather, Morrato and colleagues⁵ found that fewer than 5% of all patients met FDA contact recommendations (weekly during the first month of antidepressant therapy, biweekly during the second month, and again at 12 weeks) before the advisory and that the rate did not change afterward. The rate for the more lenient Health Plan Employer Data and Information Set (HEDIS) criteria (at least 3 visits during the 12 weeks following a prescription for an antidepressant) also did not change (60% for children, 40% for adults).

In 2 earlier studies, the same researchers reported lower rates of diagnosis and treatment of depression in children and adults after the FDA advisory.^6,7 The rate of pediatric diagnoses of depression fell to the 1999 level of 3 per 1000, the proportion of children with depression receiving no antidepressants was 3 times the rate predicted by the preadvisory trend, and SSRI prescription fills were 58% lower than predicted by the trend.⁶ The average percentage of adults with new depressive episodes (versus recurrent depressive episodes) decreased significantly, from 88.6% in the preadvisory period to 77.5% after the advisory, and the percentage of adults with depression who did not receive an antidepressant was 30% after the advisory (up from 20% in the preadvisory period).⁷

Conclusion

One can only hope that the new FDA warnings about antiseizure medications and the possible increased risk in suicidality associated with them will not result in the kind of response seen after the antidepressant warnings. Provider behavior needs to be taken into account if the public's health is to improve as more knowledge about the adverse effects of medications is obtained.

References:

References

• 1. Harris G. FDA requiring suicide studies in drug trials. N Y Times. January 24, 2008. Available at: www.nytimes.com/2008/01/24/washington/24fda. html?ei=5124&en=35daeefffa7d. Accessed March 3, 2008.
• 2. US Food and Drug Administration. Information for healthcare professionals: suicidality and antiepileptic drugs. Available at: www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm. Accessed March 6, 2008.
• 3. Rosack J. SSRI prescriptions to youth on decline since February. Psychiatr News. 2004;39:9.
• 4. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164:1356-1363.
• 5. Morrato EH, Libby AM, Orton HD, et al. Frequency of provider contact after FDA advisory on risk of pediatric suicidality with SSRIs. Am J Psychiatry. 2008;165:42-50.
• 6. Libby AM, Brent DA, Morrato EH, et al. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry. 2007;164:884-891.
• 7. Valuck RJ, Libby AM, Orton HD, et al. Spillover effects on treatment of adult depression in primary care after FDA advisory on risk of pediatric suicidality with SSRIs. Am J Psychiatry. 2007;164:1198-1205.