Suicide-Related Events in Patients Treated with Antiepileptic Drugs

The new england journal of medicine original article Suicide-Related Events in Patients Treated with Antiepileptic Drugs Alejandro Arana, M.D., Charles E. Wentworth, M.S., José L. Ayuso-Mateos, M.D., and Felix M. Arellano, M.D. Abstract From Risk MR Pharmacovigilance Services, Zaragoza (A.A., F.M.A.); the Department of Psychiatry, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid (J.L.A.-M.) all in Spain; and RiskMR, Bridgewater, NJ (C.E.W., F.M.A.). Address reprint requests to Dr. Arana at Risk MR Pharmacovigilance Services, Jerónimo Zurita 14, 1-D, 50001 Zaragoza, Spain, or at arana.riskmr@ gmail.com. N Engl J Med 2010;363:542-51. Copyright 2010 Massachusetts Medical Society. Background A previous meta-analysis of data from clinical trials showed an association between antiepileptic drugs and suicidality (suicidal ideation, behavior, or both). We used observational data to examine the association between the use or nonuse of antiepileptic drugs and suicide-related events (attempted suicides and completed suicides) in patients with epilepsy, depression, or bipolar disorder. Methods We used data collected as part of the clinical care of patients who were representative of the general population in the United Kingdom to identify patients with epilepsy, depression, or bipolar disorder and to determine whether they received antiepileptic drugs. We estimated the incidence rate of suicide-related events and used logistic regression to compute odds ratios, controlling for confounding factors. Results In a cohort of 5,130,795 patients, the incidence of suicide-related events per 100,000 person-years was 15.0 (95% confidence interval [CI], 14.6 to 15.5) among patients without epilepsy, depression, bipolar disorder, or antiepileptic-drug treatment, 38.2 (95% CI, 26.3 to 53.7) among patients with epilepsy who did not receive antiepileptic drugs, and 48.2 (95% CI, 39.4 to 58.5) among patients with epilepsy who received antiepileptic drugs. In adjusted analyses, the use of antiepileptic drugs was not associated with an increased risk of suicide-related events among patients with epilepsy (odds ratio, 0.59; 95% CI, 0.35 to 0.98) or bipolar disorder (1.13; 95% CI, 0.35 to 3.61) but was significantly associated with an increased risk among patients with depression (1.65; 95% CI, 1.24 to 2.19) and those who did not have epilepsy, depression, or bipolar disorder (2.57; 95% CI, 1.78 to 3.71). Conclusions The current use of antiepileptic drugs was not associated with an increased risk of suicide-related events among patients with epilepsy, but it was associated with an increased risk of such events among patients with depression and among those who did not have epilepsy, depression, or bipolar disorder. 542 n engl j med 363;6 nejm.org august 5, 2010

Suicide-Related Events and Antiepileptic Drugs Suicide is the 13th leading cause of death worldwide, 1 and attempted suicide is a major cause of injury. 2 Psychiatric disorders (especially affective conditions) increase the risk of suicide. 3-5 Epilepsy increases both the risk of suicide among patients with psychiatric disorders 6 and the risk of the development of psychiatric illness. 7 The early onset of epilepsy, female sex, psychiatric illness, temporal-lobe epilepsy, and inadequate neurologic follow-up are risk factors for suicide among patients with epilepsy. 6,8 Depression is common in patients with severe epilepsy, 8 but the severity of epilepsy does not necessarily correlate with the risk of suicide. 5 The risk of suicide increases soon after the onset of epilepsy 5 and then decreases gradually. Patients with long-standing epilepsy or dysphoric conditions appear to have an increased risk of suicide soon after gaining control of their seizures. 9 In January 2008, the Food and Drug Administration (FDA) issued a safety warning on the risk of suicidality associated with antiepileptic drugs. 10 The warning summarized the results of a meta-analysis of placebo-controlled clinical trials of 11 antiepileptic drugs; this meta-analysis showed a risk of the development of suicidality (primarily suicidal behavior or ideation) that was twice as high among patients who received antiepileptic drugs as among patients who received placebo. The risk increased soon after the initiation of treatment, persisted through week 24, and was elevated regardless of the type of antiepileptic drugs received and the indication for their use. The assessment of suicidality in the clinical trials that were included in the meta-analysis was subject to several limitations such as the lack of systematic or standardized language to define suicidal ideation and behavior across clinical trials. 11 We examined the association between antiepileptic drugs and suicide-related events (defined as suicide attempts and completed suicides), using data collected as part of clinical practice in the United Kingdom. Methods Study Design and Oversight The study was designed by the investigators in Spain. The data were collected by the second author, and the analyses were performed by the first and second authors. The last author wrote the manuscript. All authors reviewed the manuscript and decided before the study began to submit the manuscript for publication. Source Population and Data We performed the study using The Health Improvement Network (THIN) database, which is representative of the general population in the United Kingdom 12 and includes more than 6.7 million patients. THIN data are entered at general practitioners offices and are based on the daily record keeping of these practices. The data provide anonymous demographic, medical, and prescription information on individual patients, and they provide a longitudinal medical record for each patient. 13 Study Population Patients were eligible for inclusion in the study population if they were enrolled in a clinical practice for at least 6 months during the study period (from July 1, 1988, through March 31, 2008). A history of a suicide attempt is the major risk factor for a subsequent suicide attempt. 14 Thus, we excluded patients with a family history of suicide and a personal history of one or more suicide attempts. The study had two components. In the descriptive analysis, we estimated the crude incidence rate of suicide-related events among patients with epilepsy, depression, or bipolar disorder, with or without the use of antiepileptic drugs. We then performed a case control analysis to examine the association between the use or nonuse of antiepileptic drugs and suicide-related events. Definition of the Cohorts In the descriptive analysis, we defined the reference group as patients who did not have epilepsy, depression, or bipolar disorder and did not receive antiepileptic drugs. The other cohorts are listed in Table 1. Cohort Follow-up Patients were assigned to cohorts according to the presence of an event that defined a given cohort. The index date was the date when the last Read code 15 that would include a patient in a cohort was recorded. Patients were followed until death, loss to follow-up, or the end of the study period, whichever came first. n engl j med 363;6 nejm.org august 5, 2010 543

The new england journal of medicine Table 1. Study Cohorts. Patients who did not have epilepsy, depression, or bipolar disorder but who received antiepileptic drugs Patients with epilepsy who did not receive antiepileptic drugs Patients with epilepsy who received antiepileptic drugs Patients with depression who did not receive antiepileptic drugs Patients with depression who received antiepileptic drugs Patients with bipolar disorder who did not receive antiepileptic drugs Patients with bipolar disorder who received antiepileptic drugs Patients with epilepsy and depression who did not receive antiepileptic drugs Patients with epilepsy and depression who received antiepileptic drugs Patients with epilepsy and bipolar disorder who did not receive antiepileptic drugs Patients with epilepsy and bipolar disorder who received antiepileptic drugs Exposure to Medications The antiepileptic drugs of interest were those drugs identified in the FDA s meta-analysis which were available in the United Kingdom: carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide (felbamate was not included because it was not marketed in the United Kingdom). Current use was defined as the interval between the date of the prescription of an antiepileptic drug and 75 days after that date. After that interval, as long as no other antiepileptic drug was prescribed, the patient was considered to be a previous user. Patients without codes for antiepileptic drugs were classified as nonusers. Case Identification and Characterization Cases of suicide-related events were based on codes for suicide, attempted suicide, and intentional self-inflicted injuries plus suicide. A completed suicide was defined as a code for suicidality followed by a code for death in the following month and a final date of any administrative activity in the database or disenrollment within 6 months after the suicidality code. If the disenrollment date occurred more than 6 months after a suicidality code, we reviewed the patient s profile. Patients with a last medical or other healthrelated code that was recorded within 1 month after the suicide date were also considered to have completed suicide. Case Validation We selected a random sample of 218 cases of suicide-related events (86 suicides and 132 attempts) for validation to determine the positive predictive value of the diagnoses used. The validation process included a questionnaire sent to the general practitioner, as well as a review of the patient s medical records and death certificate when available (see the Supplementary Appendix, available with the full text of this article at NEJM.org). The questionnaires and records were reviewed by one of the investigators, who was unaware of the patients exposure to antiepileptic drugs. The positive predictive value was 97% for suicide-related events and 87% for completed suicide. This method of validating cases based on THIN data has been successfully used in other studies. 16 Selection of Controls For the case control component of the study, we randomly selected five controls from the cohort for each case patient, matched according to age at the index date (±5 years), sex, and clinical practice. Using risk-set control sampling, we defined the date of the end of the follow-up period for the controls as the date when the case patient received a diagnosis. There were no unmatched case patients. For the analysis of the use or nonuse of antiepileptic drugs within each category of illness, another set of controls, matched according to age, sex, clinical practice, and psychiatric or neurologic condition, was selected. A total of 103 case patients did not match any controls. Statistical Analysis We described the characteristics of the various cohorts using frequency tables. We calculated the incidence rates and 95% confidence intervals for suicide-related events in each of the cohorts with the use of a Poisson regression model. The relationship between the use or nonuse of antiepileptic drugs and suicide-related events (expressed as odds ratios and 95% confidence intervals) was assessed with the use of a fixedeffects conditional logistic-regression model. In addition to matching for age, sex, clinical practice, and condition when applicable, we controlled for potential confounders (Table 2) with the use of a backward-elimination process by stepwise deletion of the confounder that made the smallest change in the exposure effect estimate on deletion, provided that the effect of the confounder was 10% or less of the estimated effect. Any confounder with an effect of more than 10% 544 n engl j med 363;6 nejm.org august 5, 2010

Suicide-Related Events and Antiepileptic Drugs Table 2. Demographic Characteristics and Risk Factors for Suicide-Related Events, According to Use or Nonuse of Antiepileptic Drugs.* Variable No Epilepsy, Depression, Bipolar Disorder, or Use of Antiepileptic Drugs (N = 4,514,366) Antiepileptic Drugs Only (N = 77,319) Epilepsy Only (N = 16,120) Epilepsy and Use of Antiepileptic Drugs (N = 39,325) Male sex no. (%) 2,273,135 (50.4) 34,978 (45.2) 8,565 (53.1) 20,868 (53.1) Age no. (%) <20 yr 1,413,006 (31.3) 3,975 (5.1) 3,715 (23.0) 7,935 (20.2) 20 34 yr 1,204,371 (26.7) 7,506 (9.7) 4,786 (29.7) 8,815 (22.4) >34 64 yr 1,326,817 (29.4) 34,689 (44.9) 5,564 (34.5) 14,031 (35.7) >64 yr 500,482 (11.1) 30,848 (39.9) 1,762 (10.9) 8,008 (20.4) Data missing 69,690 (1.5) 301 (0.4) 293 (1.8) 536 (1.4) Mean age yr 32.0±23.1 56.5±20.6 35.3±20.9 41.3±23.5 Duration of time in study yr 6.2±5.3 3.9±3.9 5.4±4.9 5.4±4.7 Drug use in previous yr no. (%) Antipsychotic agent 53,894 (1.2) 7,910 (10.2) 488 (3.0) 2,588 (6.6) Antidepressant agent 103,343 (2.3) 23,034 (29.8) 810 (5.0) 3,002 (7.6) Lithium 1,146 (<0.1) 402 (0.5) 6 (<0.1) 38 (0.1) History no. (%) Drug abuse 1,232 (<0.1) 80 (0.1) 15 (0.1) 25 (0.1) Diagnosis of mental disorder 171,846 (3.8) 13,845 (17.9) 1,794 (11.1) 4,174 (10.6) Alcohol abuse 26,189 (0.6) 2,106 (2.7) 620 (3.8) 1,199 (3.0) Chronic disease score Mean score 0.45±0.97 3.26±1.96 0.68±1.20 2.09±1.51 Score no. (%) 0 3,443,036 (76.3) 1,776 (2.3) 10,801 (67.0) 973 (2.5) 1 509,052 (11.3) 16,023 (20.7) 2,236 (13.9) 18,973 (48.2) 2 329,417 (7.3) 12,478 (16.1) 1,650 (10.2) 7,111 (18.1) 3 137,521 (3.0) 14,830 (19.2) 788 (4.9) 5,644 (14.4) 4 59,001 (1.3) 12,887 (16.7) 375 (2.3) 3,468 (8.8) 5 36,339 (0.8) 19,325 (25.0) 270 (1.7) 3,156 (8.0) * Plus minus values are means ±SD. This was the reference category. Chronic disease scores can range from 0 to 5, with higher scores indicating a higher frequency of chronic disease. on the estimate was kept in the model. To control for the severity of chronic disease, we included a modified version of the chronic disease score in the model. 17,18 All analyses were conducted with the use of SAS software, version 9.1 (SAS Institute) and Stata software, version 7.0 (Stata). Results Characteristics of the Patients The cohorts included a total of 5,130,795 patients, with a total of 31,527,585 patient-years of follow-up. Table 2, and Table 1 in the Supplementary Appendix, show the demographic characteristics of the patients. Overall, 48.6% of the patients were male, and the mean (±SD) age was 33.7±23.1 years. The mean follow-up time for all the cohorts was 6.2±5.2 years. A total of 66,925 patients had epilepsy; 16,120 of these patients did not have a diagnosis of depression or bipolar disorder and did not receive antiepileptic drugs. A total of 435,790 patients with depression only and 3814 with bipolar disorder only did not receive antiepileptic drugs. A total of 77,319 pa- n engl j med 363;6 nejm.org august 5, 2010 545

The new england journal of medicine Table 3. Incidence of Suicide-Related Events, According to Cohorts and Use or Nonuse of Antiepileptic Drugs. Cohort No epilepsy, depression, or bipolar disorder All Patients Patients with First Suicide-Related Event no. of patients Person-Yr Crude Incidence Rate (95% Confidence Interval) no. of events/ 100,000 person-yr No use of antiepileptic drugs (reference group) 4,514,366 4239 28,170,361 15.05 (14.60 15.51) Any use of antiepileptic drugs 77,319 120 304,807 39.37 (32.64 47.08) Epilepsy only (no depression or bipolar disorder) No use of antiepileptic drugs 16,120 33 86,333 38.22 (26.31 53.68) Any use of antiepileptic drugs 39,325 103 213,507 48.24 (39.38 58.51) Depression only (no epilepsy or bipolar disorder) No use of antiepileptic drugs 435,790 3271 2,534,502 129.06 (124.70 133.60) Any use of antiepileptic drugs 30,772 232 130,854 177.30 (155.21 201.64) Bipolar disorder (no epilepsy) No use of antiepileptic drugs 3,814 48 22,324 215.02 (158.54 285.08) Any use of antiepileptic drugs 1,809 40 9,065 441.26 (315.24 600.87) Epilepsy and depression (no bipolar disorder) No use of antiepileptic drugs 3,392 28 16,353 171.22 (113.78 247.47) Any use of antiepileptic drugs 7,870 96 38,452 249.66 (202.23 304.88) Epilepsy and bipolar disorder No use of antiepileptic drugs 47 0 210 0 Any use of antiepileptic drugs 171 2 819 244.24 (29.58 882.28) All patients 5,130,795 8212 31,527,585 26.05 (25.49 26.62) tients received antiepileptic drugs but did not have epilepsy, depression, or bipolar disorder. The indications for the use of antiepileptic drugs in these patients were not known, although pain and pain-related diagnoses (e.g., herpes zoster) were documented in the records of 18.7% of these patients in the 30 days before prescription of the antiepileptic drugs. Incidence of Attempted and Completed Suicides A total of 8212 patients attempted suicide, including 464 patients who completed suicide. The incidence rate of suicide-related events among patients without epilepsy, depression, or bipolar disorder who did not receive antiepileptic drugs (the reference group) was 15.0 (95% confidence interval [CI], 14.6 to 15.5) per 100,000 personyears (Table 3). Details of the incidence of suicide according to the patient s psychiatric or neurologic condition are available in Table 2 in the Supplementary Appendix. The incidence rate of suicide-related events among patients who did not have epilepsy, depression, or bipolar disorder was 57.9 (95% CI, 42.8 to 76.5) per 100,000 person-years for current users of antiepileptic drugs and 32.3 (95% CI, 25.2 to 40.7) per 100,000 person-years for previous users of antiepileptic drugs (Table 4 in the Supplementary Appendix). Among patients with depression alone, the incidence rate of suicide-related events was 129.1 (95% CI, 124.7 to 133.6) per 100,000 person-years for those who were not currently receiving antiepileptic drugs and 177.3 (95% CI, 155.2 to 201.6) per 100,000 person-years for those who were receiving antiepileptic drugs. Among patients with bipolar disorder alone, the incidence rate of suicide-related events was 215.0 (95% CI, 158.5 to 285.1) per 100,000 person-years for those who were not receiving antiepileptic drugs and 441.3 (95% CI, 315.2 to 600.9) per 100,000 person-years for those who were receiving antiepileptic drugs. Among 546 n engl j med 363;6 nejm.org august 5, 2010

Suicide-Related Events and Antiepileptic Drugs patients with epilepsy alone, the incidence of suicide-related events was 38.2 (95% CI, 26.3 to 53.7) per 100,000 person-years for those who were not receiving antiepileptic drugs and 48.2 (95% CI, 39.4 to 58.5) per 100,000 person-years for those who were receiving such treatment. Figure 1 shows the probability of no suicide-related events over time in the various cohorts. The underlying illness was more strongly associated with suicide-related events than was the use or nonuse of antiepileptic drugs. Case Control Analysis The results of the case control analysis were adjusted for age; duration of illness; status with respect to previous use of antiepileptic drugs, lithium, antipsychotic drugs, or antidepressants; presence or absence of a history of alcohol abuse or a mental disorder; and chronic disease score. With adjustment for these factors, epilepsy and depression were associated with a 50% increase in the risk of suicide-related events; the risk associated with bipolar disorder was higher (Table 5 in the Supplementary Appendix). The risk of suicide-related events was increased with a history of alcohol abuse (odds ratio, 6.45; 95% CI, 5.68 to 7.32), a mental disorder (odds ratio, 2.75; 95% CI, 2.54 to 2.98), lithium use (odds ratio, 2.48; 95% CI, 1.76 to 3.49), antipsychotic-drug use (odds ratio, 1.64; 95% CI, 1.51 to 1.77), and antidepressant-drug use (odds ratio, 3.69; 95% CI, 3.42 to 3.99). Chronic diseases were clearly associated with suicide-related events, with a 20% increase in risk per unit of increase in the chronic disease score. The current use of antiepileptic drugs in patients without epilepsy, depression, or bipolar disorder was associated with an increased risk of suicide-related events (odds ratio, 2.57; 95% CI, 1.78 to 3.71). The risk of suicide-related events was elevated both among patients with epilepsy who received antiepileptic drugs and among those who did not; among patients with epilepsy and no coexisting depression or bipolar disorder who did not receive antiepileptic drugs, the odds ratio was 3.34 (95% CI, 2.34 to 4.78), and among patients with epilepsy who received antiepileptic drugs, the odds ratio was 2.31 (95% CI, 1.77 to 3.02). Similarly, the risk of suicide-related events was increased among patients with depression who were not receiving antiepileptic drugs (odds ratio, 1.58; 95% CI, 1.43 to 1.74) and among Probability of No Suicide-Related Events 1.00 0.99 0.98 0.97 0.96 Reference group Epilepsy alone Epilepsy and antiepileptic drugs Antiepileptic drugs Depression alone Depression and antiepileptic drugs Bipolar disorder and antiepileptic drugs 0.95 Bipolar disorder alone 0.00 0 10 20 Years since Treatment Initiation Figure 1. Kaplan Meier Estimates of the Probability of No Suicide-Related Events over Time, According to Cohort. those who were receiving such treatment (odds ratio, 2.06; 95% CI, 1.36 to 3.11) and among patients with bipolar disorder who were not receiving antiepileptic drugs (odds ratio, 2.44; 95% CI, 1.48 to 4.03) and among those who were (odds ratio, 3.77; 1.24 to 11.43) (Table 4 and Fig. 2). As compared with patients with bipolar disorder who received neither lithium nor antiepileptic drugs, the odds ratio for suicide-related events was 0.56 (95% CI, 0.11 to 1.71) among patients with bipolar disorder who received antiepileptic drugs and lithium and 0.74 (95% CI, 0.45 to 1.19) among those who received lithium alone. In a series of separate case control analyses, we observed no significant increase in the risk of suicide-related events among current users of antiepileptic drugs as compared with nonusers in the subgroup of patients with epilepsy alone (odds ratio, 0.59; 95% CI, 0.35 to 0.98), the subgroup of patients with bipolar disorder alone (odds ratio, 1.13; 95% CI, 0.35 to 3.61), or the subgroup of patients with epilepsy and depression (odds ratio, 1.24; 95% CI, 0.56 to 2.72). Among patients with depression alone, the use of antiepileptic drugs was significantly associated with an increased risk of suicide-related events (odds ratio, 1.65; 95% CI, 1.24 to 2.19) (Table 5). The effects of the use of various antiepileptic drugs are shown in Table 6 in the Supplementary Appendix. n engl j med 363;6 nejm.org august 5, 2010 547

The new england journal of medicine Table 4. Combined Effect of Use of Antiepileptic Drugs and Various Conditions on the Risk of Suicide-Related Events, Adjusted for Covariates.* Cohort No epilepsy, depression, or bipolar disorder Case Patients Controls Odds Ratio (95% CI) number No use of antiepileptic drugs (reference group) 5,948 45,620 1.00 Current use of antiepileptic drugs 76 84 2.57 (1.78 3.71) Epilepsy only (no depression or bipolar disorder) No use of antiepileptic drugs 64 168 3.34 (2.34 4.78) Current use of antiepileptic drugs 134 380 2.31 (1.77 3.02) Depression only (no epilepsy or bipolar disorder) No use of antiepileptic drugs 3,475 4,448 1.58 (1.43 1.74) Current use of antiepileptic drugs 239 159 2.06 (1.36 3.11) Bipolar disorder only (no epilepsy) No use of antiepileptic drugs 60 42 2.44 (1.48 4.03) Current use of antiepileptic drugs 40 7 3.77 (1.24 11.43) Epilepsy and depression (no bipolar disorder) No use of antiepileptic drugs 33 37 1.60 (0.91 2.81) Current use of antiepileptic drugs 93 59 2.82 (1.71 4.67) Epilepsy and bipolar disorder No use of antiepileptic drugs 0 1 0 Current use of antiepileptic drugs 2 0 Infinite * Odds ratios were derived from one conditional logistic-regression model with matching according to age (±5 years), sex, and clinical practice. Odds ratios were adjusted for age, duration of disease, previous use of antiepileptic drugs, lithium, antipsychotic drugs, or antidepressants; presence or absence of a history of alcohol abuse or a mental disorder; and chronic disease score. Discussion 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 suiciderelated 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 personyears, 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 painrelated (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. 21 548 n engl j med 363;6 nejm.org august 5, 2010

Suicide-Related Events and Antiepileptic Drugs 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 metaanalysis, 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 metaanalysis, 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 bias 11 and the increased frequency of suicide in the first month after initiation of antidepressant treatment. 26 Since most clinical trials have a short duration Odds Ratio 100.0 10.0 1.0 0.1 No use of antiepileptic drugs No Disorder Epilepsy Depression Bipolar Disorder 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 Current use of antiepileptic drugs Figure 2. Effect of Current Antiepileptic-Drug Use on the Risk of Suicide- Related Events. The risk is shown according to disease status (epilepsy, depression, bipolar disorder, or none of these conditions). The bars indicate 95% confidence intervals. n engl j med 363;6 nejm.org august 5, 2010 549

The new england journal of medicine Table 5. Association between Current Use of Antiepileptic Drugs and Suicide-Related Events in Each of the Cohorts, Adjusted for Covariates.* Cohort Epilepsy only (no depression or bipolar disorder) Case Patients Controls Odds Ratio (95% CI) P Value number No use of antiepileptic drugs 64 282 1.00 Current use of antiepileptic drugs 104 399 0.59 (0.35 0.98) 0.04 Depression only (no epilepsy or bipolar disorder) No use of antiepileptic drugs 3475 17,747 1.00 Current use of antiepileptic drugs 99 157 1.65 (1.24 2.19) 0.001 Bipolar disorder only (no epilepsy) No use of antiepileptic drugs 60 65 1.00 Current use of antiepileptic drugs 17 14 1.13 (0.35 3.61) 0.84 Epilepsy and depression (no bipolar disorder) No use of antiepileptic drugs 33 64 1.00 Current use of antiepileptic drugs 61 85 1.24 (0.56 2.72) 0.60 Epilepsy and bipolar disorder No use of antiepileptic drugs 0 0 1.00 Current use of antiepileptic drugs 1 0 Infinite (0.00) Infinite * Odds ratios were derived from conditional logistic-regression models matched according to diagnostic category, age (±5 years), sex, and clinical practice. Odds ratios were adjusted for age; duration of disease; previous use of antiepileptic drugs, lithium, antipsychotic drugs, or antidepressants; presence or absence of a history of alcohol abuse or a mental disorder; and chronic disease score. A total of 103 case patients did not match any controls. 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 suiciderelated events among patients with depression and among patients who did not have epilepsy, depression, or bipolar disorder. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Delories Dunn, Dr. Janet Price, and Dr. Randal Marshall for their suggestions for revisions of an earlier version of the manuscript. References 1. DeLeo D, Bertolote J, Lester D. Selfdirected violence. In: Krug EG, Dahlberg LL, Mercy JA, Zwi AB, Lozano R, eds. World report on violence and health. Geneva: World Health Organization, 2002: 183-212. (Accessed July 9, 2010, at http:// www.who.int/violence_injury_prevention/ violence/world_report/en/index.html.) 2. Moscicki EK. Epidemiology of suicidal behavior. In: Silverman MM, Maris RW, eds. Suicide prevention: toward the year 2000. New York: Guilford, 1985:22-35. 550 n engl j med 363;6 nejm.org august 5, 2010

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