Suicide is the tenth leading cause of death worldwide,1 with approximately 800,000-1,000,000 people succumbing annually and a mortality rate of 11.6 per 100,000 persons per year.2 The Organization for Economic Co-operation and Development (OECD) has reported that suicide is a significant cause of death in many OECD countries, accounting for over 150,000 deaths in 2011.3 Korea has the highest suicide rate of the 34 OECD countries, at 33.3 deaths per 100,000 population.3 Although suicide rates have decreased by more than 20% across OECD countries since 1990,3 the rate has continued to increase in Korea, where suicide has become the fourth leading cause of death.4 Psychiatric disorders, and notably depression, anxiety, psychotic, and personality disorders, are well known as the main risk factors for suicide.1 Therefore, close observation and management of high-risk populations with psychiatric disorders are mandatory for reducing the suicide rate.

People with epilepsy (PWE) have a high risk of developing psychiatric disorders. According to a review of the literature, 9-37% of PWE meet the criteria for depression and 11-25% for anxiety, compared to 6-19% and 7-11%, respectively, of the general population or people without epilepsy (PWoE).5 A Korean hospital-based study found that the risk of developing depression is 3.2-fold higher and the risk of developing anxiety is 4.8-fold higher in PWE than in healthy controls.6 Along with the high prevalence of psychiatric disorders, PWE appear to have a higher risk of developing suicidality, with suicidal ideation and suicide attempts, than do PWoE. A Canadian population-based study exploring numerous aspects of mental health in PWE in the community found that the lifetime prevalence of suicidal ideation is 25%, which is almost two times higher than that for PWoE.7 A Danish population-based study found that the risk of committing suicide is three times higher among PWE than in the general population,8 and a Korean hospital-based survey at two tertiary-care centers found that suicidal ideation is 3.6 times more common in PWE than in healthy controls.6 Although suicidal ideation may be a significant warning sign for suicide attempts, most people who experience suicidal ideation do not actually commit suicide.9 Therefore, investigations of suicide should include the characteristics of suicide attempts, such as the frequency, number, and method of suicide attempts. However, these characteristics were not evaluated in the aforementioned Korean study.

According to studies carried out in the US and Europe, the major risk factors for suicidality are psychiatric disorders or psychiatric symptoms.8,10,11 The following seizure-related parameters have also been proposed as risk factors: daily dose, type, or number of antiepileptic drugs (AEDs), socioeconomic status, and female gender.8,11,12 The use of AEDs has been high-lighted as a potential risk factor.13 In 2008, the US Food and Drug Administration reported a twofold increased risk of suicidal ideation or suicide attempts for 11 AEDs [odds ratio (OR)=1.80 and 95% confidence interval (CI)=1.24-2.66].14 However, the available data are not methodologically strong enough to support or reject the claimed increased risk of suicidality with AEDs.15 Given the controversy regarding the impact of AEDs on suicidality, a study of the adverse effects of AEDs as a risk factor for suicidality may additionally provide evidence to resolve that issue. In Korea, the risk factors for suicide have been investigated in only one hospital-based study in which 257 PWE were recruited, which demonstrated that the strongest predictor for suicidal ideation was depression symptoms, followed by obsessive-compulsive symptoms, hostility, and paranoid ideation; seizure-related factors did not appear to contribute to suicidal ideation.16 The limitations of that study were that the socioeconomic status and adverse effects of AEDs were not considered as variables contributing to suicidal ideation, and the risk factors for suicide attempts were not examined. Therefore, studies are required to determine the risk factors for suicidality, including suicidal ideation and suicide attempts, in which the effects of socioeconomic status and adverse effects of AEDs are also considered.

While many population- or hospital-based studies have been conducted in Western countries to investigate suicidality and its risk factors in PWE,17 such studies involving large numbers of PWE have not been performed in Korea. Furthermore, the proportion of patients with suicidality who actually receive a psychiatric intervention in Korea has not been established. Therefore, the aims of the present multicenter trial were to determine the characteristics of suicidality in a large number of Korean PWE, examine the frequency of psychiatric interventions among PWE with suicidality, and to establish the involved risk factors.

In total, 825 PWE were initially enrolled in the study, of which 141 were excluded due to refusal to participate in the study (n=32), inability to complete the interviews or questionnaire because of mental retardation (n=47) or serious medical or neurological diseases (n=43), and old age (n=19). Therefore, 684 PWE (mean age, 41.5 years; 57.6% male) were ultimately included. In addition, 229 PWoE (mean age, 41.4 years; 57.2% male) were also invited to participate in the study. The demographic and clinical characteristics of all of the study subjects are listed in Table 1. The levels of education, employment, household income, driving license ownership, and marriage were lower for PWE than for PWoE. Concurrent medical diseases were present in 146 PWE (21.3%), and included diabetes and other endocrinologic disorders (n=41), hypertension and other cardiovascular disorders (n=37), cerebrovascular disease and other neurological disorders (n=24), hepatic and gastrointestinal disorders (n=20), renal disorders (n=8), and other diseases (n=47). Concurrent medical diseases were present in 46 PWoE (20.1%), and included diabetes and other endocrinologic disorders (n=11), hypertension and other cardiovascular disorders (n=8), cerebrovascular disease and other neurological disorders (n=7), hepatic and gastrointestinal disorders (n=6), renal disorders (n=3), and other diseases (n=11). Partial onset of seizures and cryptogenic/symptomatic etiologies were more prevalent among PWE than generalized seizures and idiopathic etiology. Of the PWE, 61% had experienced 1 year of seizure freedom. MRI abnormalities were found in 276 (40.4%) PWE, and the etiologies of these abnormalities were hippocampal sclerosis (n=78), vascular lesions (n=54), traumatic injury (n=47), congenital anomalies (n=44), infection (n=36), tumor (n=8), and others (n=32). The duration of AED intake was 14.0±12.1 years (mean±SD; range, 1-54 years), and almost 50% of the patients received AED monotherapy. The AED load was 1.5±1.2 (range 0.1-7.7). With respect to adverse effects, 61.5% of the patients scored K-LAEP items with 3 or 4 points.

The probabilities of current MDD and GAD and suicidality for PWE and PWoE are given in Table 2. The frequencies of current MDD and GAD were 21.9% and 18.6% in PWE, respectively, and were 4.7 times and 6.3 times higher than for PWoE. The frequency of suicidality was 30.4% in PWE, which was 4.6 times higher than that in PWoE. The degree of suicidality did not differ between PWE and PWoE. Suicidal ideation without a suicide attempt was reported by 100 PWE (14.6%), and combined issues manifested in 108 PWE (15.8%). Among the 108 PWE who attempted suicide, 64 (59.3%) had made a single attempt, 17 (15.7%) had made two attempts, 8 (7.4%) had made 3 attempts, and 19 (17.6%) had attempted suicide more than 3 times. In total, 40.7% of patients who attempted suicide had done so more than once.

The methods of suicide attempt are illustrated in Fig. 1. The most common method of suicide attempt was drug overdose (n=46, 34.9%), followed by cutting or stabbing (n=25, 18.9%), hanging (n=17, 12.9%), jumping (n=14, 10.6%), poisoning (n=10, 7.6%), drowning (n=9, 6.8%), vehicular impact (n=6, 4.5%), and others (n=5, 3.8%). The drugs used in drug overdoses were psychiatric drugs (n=24, 18.2%), medical drugs (n=15, 11.4%), and AEDs (n=7, 5.3%).

The frequency of psychiatric interventions among PWE with suicidality is shown in Fig. 2. Among 208 PWE who were suicidal, 38 patients (18.3%) had previously undergone or were currently undergoing a psychiatric intervention. However, 4 patients (1.9%) were only currently receiving an intervention and 30 (14.4%) had only received an intervention previously. Unfortunately, 136 patients (65.4%) had never received any psychiatric intervention.

The factors associated with suicidality in PWE according to univariate analysis are summarized in Table 3. Suicidality was significantly associated with female gender, unemployment, low household income, no driver's license, being unmarried, divorced, or bereaved, early age of onset, large number of AEDs (monotherapy vs. triple therapy), cryptogenic/symptomatic etiology, poor seizure control (WCE vs. UCE), history of febrile convulsion, high AED load, MDD, GAD, and item(s) scoring 3 or 4 on the K-LAEP.

The risk factors for suicidality revealed multivariate logistic regression analysis are listed in Table 4. The most powerful risk factor for suicidality was MDD (OR=6.448, 95% CI=3.739-11.120, p<0.001), followed by GAD (OR=3.561, 95% CI=1.966-6.452, p<0.001), item(s) scoring 3 or 4 on the K-LAEP (OR=2.688, 95% CI=1.647-4.387, p<0.001), and a history of febrile convulsion (OR=2.188, CI=1.318-3.632, p=0.002). The probability of suicidality with respect to the combination of three main risk factors of MDD, GAD, and item(s) scoring 3 or 4 on the K-LAEP is given in Table 5. If the patient had MDD, GAD, and item(s) scoring 3 or 4 on the K-LAEP, the probability of suicidality was 45.5-fold higher compared to patients with none of these risk factors (p<0.001). The probability of suicidality was also 22.6-fold higher when the patient had two risk factors, such as MDD/GAD, MDD/item(s) scoring 3 or 4 on the K-LAEP, or GAD/item(s) scoring 3 or 4 on the K-LAEP (p<0.001). However, it increased only 2.9-fold when the patient had only one of these risk factors (p<0.001). Although patients who had three risk factors appeared more likely to have increased suicidality than those patients who had only two risk factors, the difference was not statistically significant.

This is the first study to investigate the characteristics of suicidality among PWE living in Korea. Over 30% of the included PWE had suicidality, and this rate was 4.6 times higher than that of PWoE. Almost 16% of patients had attempted suicide, and GAD was closely related to the number of suicide attempts. Drug overdose was the most common method of suicide attempt. Almost two-thirds of patients had not received psychiatric interventions at the time of enrollment. The main risk factors contributing to suicidality were MDD, GAD, and item(s) scoring 3 or 4 on the K-LAEP score. Clinicians should thus always pay attention to possible psychiatric problems and the adverse effects of AEDs in PWE, and manage them appropriately in an attempt to reduce the risk of suicidal ideation or suicide attempts.

Population-based, case-control studies have revealed that the frequency of psychiatric diseases is increased in PWE.7,8 In a Korean hospital-based study, PWE had 3.2- and 4.8-fold higher risks of developing depression and anxiety symptoms, respectively, than healthy controls.6 In the present study, the frequencies of current MDD and GAD were 21.9% and 18.6%, respectively, in PWE, and they were 4.7 and 6.3 times higher than those in PWoE. The differences in these frequencies of MDD and GAD can be explained by differences in their methods of assessment. The MINI interview was conducted herein to identify depression and anxiety, rather than a self-reported questionnaire.

In this study, 30.4% of PWE had suicidality, which is higher than the lifetime prevalence of suicidal ideation in Canadian PWE,7 probably because suicidality in this study included both suicidal ideation and suicide attempts. A suicide attempt is a significant risk factor for completed suicide, and completed suicide is an important contributor to increased mortality.10 This means that it is necessary to investigate both suicide attempts and suicidal ideation. A retrospective cohort study in the UK found that 51% of PWE attempted suicide more than once during the 15-year observation period, with this frequency being 1.6 times higher than that in PWoE.27 In the present study, 40.7% of patients who attempted suicide tried to do so more than once. Although this was a cross-sectional study, we presumed that many PWE were likely to repeatedly attempt suicide. The number of suicide attempts was not counted for PWoE, and so it was not possible to identify whether the number of repeated suicide attempts was higher in PWE than in PWoE.

The methods of suicide in PWE were determined in this study. A previous study involving a general population found that the most common methods of suicide were hanging, poisoning, and self-immolation.28 In Singapore, jumping is the most frequent method.29 In countries with larger rural populations, such as India and the Republic of Korea, poisoning (usually by pesticides) is common.30,31 In a recent brief report on suicide by the Korean Ministry of Health and Welfare, the most frequent method of suicide attempt in people who visited an emergency room was drug ingestion (55.9%), followed by stabbing with a knife or sharpener (14%) and poisoning by agricultural chemicals (12.2%).32 A UK study on PWE found that 94% of self-harmed PWE had poisoned themselves, whereas only 33% of self-harming PWE had injured themselves.27 The present study revealed the same tendency as the UK study, with the frequency of drug overdose and poisoning being higher than for self-injury (42.5% vs. 18.9%).

While comorbid psychiatric disorders and suicidality in PWE have been found in many studies, a significant proportion of patients has not been appropriately diagnosed or treated by clinicians. In a hospital-based study assessing the impact of sertraline on the severity and frequency of seizures in PWE, 50% of patients diagnosed with MDD at enrollment did not have a previous history thereof.33 In a multicenter trial evaluating psychiatric morbidity in chronic epilepsy, only 43.3% of patients diagnosed with a current MDD were taking an antidepressant medication.34 A hospital-based study investigating psychiatric disorders in patients with complex partial seizure revealed that 42.9% of patients with a current MDD had never received treatment.35 Furthermore, in a survey of the approach used by clinicians to suicidality and depression in PWE, almost 62% did not use a scale to routinely screen for depression in PWE.36 Among the respondents, only 17% asked their visiting patients about suicidality, and 47% queried about suicidality only among patients with depression. Approximately 42% of the patients did not feel comfortable receiving treatment for depression. A recent retrospective cohort study in the UK found that 30% of PWE reported harming themselves, as defined by intentional self-poisoning, self-injury, or both, and they did not undergo psychiatric treatment.27 The present study found that 65.4% of PWE with suicidality did not receive any psychiatric intervention. This means that suicidality is much more likely to be underrecognized in Korean PWE than among PWE in at least some Western countries. There is a high suicide rate among the Korean population, and so clinicians should address PWE as a population at a high risk of attempting suicide. We therefore strongly recommend that clinicians screen for suicidality in PWE. The suicidality module of the MINI is a short, efficient diagnostic interview designed to detect suicidal ideation, suicidal plans, and suicide attempts,25 and it can be applied to PWE.10 If there is insufficient time to perform such an interview, then we recommend that physicians use the suicide item of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E; i.e., item 4 of the NDDI-E: "I'd be better off dead").37 The findings of the present study may help to alert clinicians to PWE who are at risk of suicide, and may thus promote further assessment or appropriate referrals.

Many studies have found that the frequency of psychiatric diseases is elevated among PWE,5,6,7 and that psychiatric problems are the strongest risk factors for suicide.8,10,11,16 We also found that MDD is the strongest predictor of suicidality in PWE, followed by GAD. Brief screening tools, such as the NDDI-E and the seven-item GAD questionnaire, are adequate for identifying depression and anxiety in a busy clinical setting.38,39

A unique finding of the present study is that the adverse effect of AEDs is a major risk factor for suicidality. However, there is no definite proof for increased suicidality in PWE taking AEDs;15 instead, depression and anxiety exacerbate the adverse effects of AEDs,40 and hence psychiatric problems may play a role in these findings. Further investigation into the relationship between suicidality and AEDs after adjusting for psychiatric disorders is needed. We recommend the use of the K-LAEP for identifying the adverse effects of AEDs in a busy clinical setting.24 A history of febrile convulsion was also found in this study to be a risk factor for suicidality. Prolonged febrile seizures are reportedly associated with acute hippocampal injury, an increased risk of epilepsy, and medial temporal sclerosis.41 Since hippocampal injury is associated with depression and suicide,42 a history of febrile convulsions might be likely to produce suicidality.

A limitation of this study was the inclusion of a relatively small sample. However, this is the first study to investigate the characteristics of suicidality in PWE living in Korea, and we have demonstrated that suicidality is more prevalent in PWE than in PWoE. Despite suicide being an important contributor to the increased mortality in PWE,8 we have shown here that Korean clinicians tend to overlook suicidality in this patient group. We recommend that clinicians should routinely ask PWE about suicidal ideation and their history (if any) of suicide attempts and, if suicidal ideation and suicide attempts are suspected, they should apply appropriate psychiatric interventions. Since Korean psychiatrists do not generally treat PWE, the neurologists caring for such patients should consult with psychiatrists and/or address the underlying psychiatric issues. Thus, communication and cooperation between neurologists and psychiatrists is crucial to the success of timely recognition and treatment of this potential mental health issue among PWE.