Our analyses of observational data collected as part of clinical practice in the United Kingdom confirmed the previously reported increased risk of suicide-related events associated with epilepsy, depression, and bipolar disorder.19 Our findings suggest that treatment with antiepileptic drugs does not confer an additional risk of suicide-related events among patients with epilepsy.

The crude incidence of suicide-related events among patients with epilepsy who did not receive antiepileptic drugs was 38.2 per 100,000 person-years, and the incidence was slightly higher (48.2 per 100,000 person-years) among patients with epilepsy who received antiepileptic drugs. The most likely explanation for the difference between the unadjusted and adjusted findings is that patients who received antiepileptic drugs were older and had more coexisting conditions and risk factors than those who did not receive antiepileptic drugs (Table 2); we controlled for these factors in the case−control analysis.

The risk of suicide-related events was increased among patients who received antiepileptic drugs for indications other than epilepsy, bipolar disorder, or depression (odds ratio, 2.57; 95% CI, 1.78 to 3.71). It is not possible to be certain about the indications for the use of antiepileptic drugs in these patients, but it is likely that for some patients the indications were pain-related (e.g., herpes zoster). Pain, especially chronic pain, has been associated with an increased risk of suicide.20 In patients with depression, the risk was also higher among current users of antiepileptic drugs than among nonusers. Although a causal role of antiepileptic drugs is possible, it is also possible that the use of antiepileptic drugs in these patients is a marker of severe depression or the presence of another condition that may be associated with an increased risk of suicide-related events.21

A study has suggested that the risk of suicide associated with bipolar disorder is lower during treatment with lithium than with other treatments.22 This finding was also observed in our study; however, the number of patients who received lithium was too low (29 patients overall) to draw firm conclusions. Among patients with bipolar disorder in our study, the odds ratio for suicide-related events was 0.56 (95% CI, 0.11 to 1.71) among those who received antiepileptic drugs and lithium and 0.74 (95% CI, 0.45 to 1.19) among those who received lithium alone, as compared with patients who received neither lithium nor antiepileptic drugs. However, the number of case patients who received lithium was low (29 overall).

In general, our results do not confirm the findings previously reported by the FDA.10 The FDA study was a meta-analysis of data from placebo-controlled clinical trials of the use of antiepileptic drugs across a number of indications for up to 24 weeks. Among the 142 cases of suicide-related events included in the meta-analysis, 4 (2.8%) were completed suicides and 38 (26.8%) were suicide attempts. Our study focused on these “harder” end points that are of greatest clinical concern and involved a longer follow-up (mean, 6.2 years). Unlike the FDA meta-analysis, our results suggest that in patients with epilepsy, the use of antiepileptic drugs is not associated with an increased risk of suicide attempts or completed suicide. Our results were similar for patients with bipolar disorder: we did not detect a significant effect of antiepileptic drugs on suicide-related events among patients with this condition, which is associated with a high risk of suicide,23 although our results had wide confidence intervals. We could not rule out a large association, since the upper bound of the 95% confidence interval for the odds ratio exceeded 3, but we also could not rule out a “protective” effect, since the lower confidence limit was 0.35. Our findings in bipolar disorder were consistent with those of other studies.24 Differences between the results of a meta-analysis conducted by the FDA and epidemiologic studies of suicidality have also been reported with regard to antidepressants.25 Reasons for these differences include ascertainment bias11 and the increased frequency of suicide in the first month after initiation of antidepressant treatment.26 Since most clinical trials have a short duration of treatment and epidemiologic studies have a long follow-up, the incidence of these early-occurring suicides becomes diluted in epidemiologic studies as compared with clinical trials.

The incidence rate of completed suicide in our population was 1.5 per 100,000 patient-years. In 2007, the incidence rate was 16.8 per 100,000 among men and 5.0 per 100,000 among women in the United Kingdom.27 Potential explanations for the lower incidence of suicide in our cohort include the fact that we calculated the incidence rate of suicide after excluding from the sample patients with a family history of suicide or a personal history of suicide attempts and the fact that suicide has been shown to be underreported in THIN.28 Underreporting would not have a major effect on the associations observed in our case−control analyses unless it affected some cohorts more than others. The high positive predictive value for the diagnosis of suicide-related events in the case validation supports the validity of our study.

An increased risk of suicide-related events among patients receiving specific antiepileptic drugs as compared with patients receiving topiramate for any indication has recently been reported.29 This study addressed a different question and used substantially different methods. For a patient who is being treated with antiepileptic drugs, the risk of suicide results from the combination of the risk associated with the illness prompting the use of these drugs and the risk associated with the drugs themselves. Our results, stratified according to the indication for drug use, suggest that illness carries more importance than the use of antiepileptic drugs. The results of our analysis of individual antiepileptic drugs were imprecise, with wide confidence intervals, but they point to differences in risk associated with antiepileptic drugs used for various indications.

To minimize confounding, we excluded from the analysis those patients with a history of suicide-related events, so it is theoretically possible that our results cannot be extrapolated to this high-risk population. Although we tried to limit confounding, some of the results may be partially attributable to confounding by indication.30 For example, the increased risk observed among patients with pain may be due to an effect of antiepileptic drugs or may simply reflect the fact that patients with pain, which is associated with an increased risk of suicide, received antiepileptic drugs. The way we built our cohorts, with no overlap of subjects between cohorts, may have led to immortal time bias. This bias was avoided in the case−control analysis.

In conclusion, our findings do not provide support for an association between antiepileptic drugs and suicide-related events among patients receiving antiepileptic drugs for epilepsy. However, we did observe an association between the current use of antiepileptic drugs and suicide-related events among patients with depression and among patients who did not have epilepsy, depression, or bipolar disorder.