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Effects of seizure frequency, depression and generalized anxiety on suicidal tendency in people with epilepsy
Epilepsy Research 160 (2020) 106265
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Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Effects of seizure frequency, depression and generalized anxiety on suicidal tendency in people with epilepsy
T
Xing Liu, Hongnian Chen, Zheng Xiao* Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, NO.1 Yixueyuan Rd. Yuzhong District, 400016, Chongqing, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Seizure frequency Depression Generalized anxiety Suicidal tendency Epilepsy
Purpose: The highest risk of suicide was identified among patients diagnosed with both epilepsy and comorbid psychiatric disease. The most common comorbid psychiatric conditions of epilepsy are anxiety and depression. This study examines whether and how seizure frequency, depression and generalized anxiety interact to influence suicidal tendency. Methods: A consecutive cohort of PWE was recruited from the First Affiliated Hospital of Chongqing Medical University. Each patient completed the Neurological Disorders Depression Inventory for Epilepsy scale[NDDI-E], the Generalized Anxiety Disorder-7 (GAD-7), and the suicidality module of Mini-International Neuropsychiatric Interview(MINI) v.5.0.0. Spearman’s correlation and moderated mediation analysis were used to examine the associations among seizure frequency, depression, generalized anxiety and suicidal tendency. Results: Seizure frequency was positively associated with suicidal tendency. Depression severity partially mediated the relationship between seizure frequency and suicidal tendency. The indirect effect of seizure frequency on suicidal tendency was positive, and accounted for 50.2 % of the total effect of seizure frequency on suicidal tendency. The indirect effect of seizure frequency on suicidal tendency through depression severity was positively moderated by generalized anxiety severity. Conclusions: Reducing seizure frequency may be the basis of suicide prevention in PWE. At the same time, the effect of seizure frequency on suicidal tendency can be partially explained by the mediation of depression severity, and the magnitude of the indirect effect of seizure frequency on suicidal tendency was contingent upon generalized anxiety severity. In addition to depression severity, generalized anxiety severity also exerts an important effect on suicidal tendency in PWE.
1. Introduction The prevalence of suicidal thoughts is 2–3 times higher in PWE than in those without epilepsy (Tellez-Zenteno Jose et al., 2007; Christensen et al., 2007). The highest risk of suicide was identified among patients diagnosed with both epilepsy and comorbid psychiatric disease (especially affective disorders) (Christensen et al., 2007). Moreover, the most common comorbid psychiatric conditions of epilepsy are major depression (17.4 %)and anxiety(22.8 %) (Tellez-Zenteno Jose et al., 2007). A recent cross-sectional study in China found that depression was an independent risk factor of suicide risk in PWE (Li et al., 2019). However, It was worrying that about 44 % of PWE reported they would not seek help when they were feeling stressed, worried, or low (Margrove Kerrie et al., 2011). In west China, the treatment gap of
depression in PWE was up to 72.5 % (Li et al., 2019). Therefore, it is taken for granted that more attention should be paid to comorbid depression in PWE. Besides, it is worthy of note that the current seizure frequency has significant associations with levels of depression (Jacoby et al.,1996). And high seizure frequency is an independent risk factor of depression (Kimiskidis Vasilios et al., 2007). One possible explanation may lay in that the learned helplessness due to the uncertainty and unpredictability of seizures, and the chronic stress exposure owing to the 'burden of epilepsy, might facilitate the development of depression (Hoppe and Elger Christian, 2011). Logically, we posit that seizure frequency will be positively associated with the severity of depression. And depression severity, in turn, will be positively associated with suicidal tendency. However prior studies reported that the major predictor of suicidal
Abbreviations: PWE, people with epilepsy; AEDs, antiepileptic drugs; NDDI-E, the neurological disorders depression inventory for epilepsy; GAD-7, the generalized anxiety disorder-7 ⁎ Corresponding author. E-mail address: [email protected] (X. Zheng). https://doi.org/10.1016/j.eplepsyres.2020.106265 Received 8 November 2019; Received in revised form 30 December 2019; Accepted 1 January 2020 Available online 03 January 2020 0920-1211/ © 2020 Elsevier B.V. All rights reserved.
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Fig. 1. illustration of proposed moderated-mediation conceptual model.
neurological/psychiatric disorders (eg, aphasia, schizophrenia) that could hamper accurate completion of the questionnaires.
ideation in PWE was depression rather than seizure-related variables (Lim et al., 2010；Hecimovic et al.,2012), therefore the relationship between seizure frequency and suicidal tendency deserves further research. On the other hand, a population-based longitudinal study found that comorbid anxiety disorders amplified the risk of suicide attempts in persons with mood disorders (Sareen et al., 2005). Coincidently, a recent study found that the co-occurrence of mood and anxiety disorders was the greatest risk factor of suicidal behaviors in general population (Wang et al., 2018). One reason may be that persons with anxiety disorder were at increased risk for deliberate self-harm, including suicide attempts (Chartrand et al., 2012). Therefore, we speculate that anxiety would interact with depression to increase suicidal tendency. Nevertheless, anxiety disorders in PWE have received far less attention than depression, and are ever called the “forgotten comorbidity” in PWE (Kanner Andres, 2011). Up to now, there have been few studies on how anxiety influences suicidal tendency in PWE. In the current study, we propose a conceptual model (see Fig.1)：(a)to test whether depression severity would mediate the association between seizure frequency and suicidal tendency, and(b)to test whether the indirect effect of seizure frequency on suicidal tendency through the mediation of depression severity would be moderated by generalized anxiety severity. Based on the literatures reviewed above, we propose the following hypotheses, H1：seizure frequency would increase depression severity, which in turn increases suicidal tendency. In other words, depression severity would mediate the association between seizure frequency and suicidal tendency；H2：Generalized anxiety severity would be positively associated with suicidal tendency. Furthermore, the positive relationship between depression severity and suicidal tendency would be stronger for PWE in high level of generalized anxiety severity than for PWE in low level of generalized anxiety severity.
2.2. Measures 2.2.1. The neurological disorders depression inventory for epilepsy (NDDIE) The NDDI-E is an epilepsy-specific self-rating questionnaire specifically developed to rapidly screen the symptoms of depression in the past two weeks in epilepsy clinic. It consists of six items reflecting depressive symptoms that can be differentiated from common side effects of AEDs (e.g., fatigue or experiencing cognitive problems) (Gilliam Frank et al., 2006). Each item is assigned a score of 1-4, which indicates 4 ranks from “never” to “always/often”. The total score ranges from 6 to 24, with a higher score corresponding to a higher depression severity. The NDDI-E has been validated in 13 languages (Gill Stephanie et al., 2017), including Chinese (Guo et al., 2015a, b; Tong et al., 2015). The validation studies of the NDDI-E have identified different cutoff scores for major depression, ranging from > 11 to > 16 (Kim et al., 2019).The NDDI-E was recommended to screen PWE for depression in International consensus clinical practice statements (Kerr Mike et al., 2011).
2.1. Participants
2.2.2. The generalized anxiety Disorder-7 (GAD-7) GAD-7 is a seven-item self-rating instrument developed to rapidly identify symptoms of generalized anxiety disorders in primary care sites. Its items describe the typical symptoms of general anxiety disorder (GAD) and rate on a 4-point scale, from “Not at all” to “Nearly every day”. A higher score represents higher anxiety severity. In the original study, a score of 10 or greater on the GAD-7 represents an optimal cut point for GAD (Spitzer Robert et al., 2006). It has been validated in patients with epilepsy in China, Korea and France, with a cut-off score of > 6 or > 7 for GAD (Tong et al., 2016; Seo et al., 2014; Micoulaud-Franchi et al., 2016). GAD-7 was one of the recommended instruments to screen PWE for anxiety (Hesdorffer Dale and Kanner Andres, 2009).
Participants were consecutively recruited from the epilepsy clinic of the First Affiliated Hospital of Chongqing Medical University, a large tertiary care hospital, from March to August 2019. The study protocol and consent forms were approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. Inclusion criteria were :(1)diagnosis of epilepsy according to the International League Against Epilepsy (ILAE) criteria (Fisher Robert et al., 2014). (2) age 18 years or older, (3) having received stable dose of one or more antiepileptic drugs for at least the past 30 days. (4) having received at least 6 years of education so that they have enough reading ability to complete the questionnaires. (5) willingness to provide written informed consent to participate the experimental procedures. Exclusion criteria were: (1) the Mini-Mental State Examination (MMSE) score is less than 20 for Participants being educated for 6 years, and less than 24 for those being educated for 7 or more years.(2) presence of significant
2.2.3. Mini-International neuropsychiatric interview (MINI) The MINI is brief, structured psychiatric diagnostic interviews compatible with the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV) and the International Classification of Diseases10(ICD-10)criteria. The MINI mainly explores DSM Axis I disorders and antisocial personality disorder(Sheehan et al.,1998).The suicide module of the MINI (Chinese version 5.0.0) focuses on current suicidal ideation and attempt in the past 4 weeks. It contains six questions, three of which are about suicide ideation, one about suicide plan, and two about suicide attempt within the past 4 weeks or in their lifetime. The total scores range from 0 to 33, with a higher score corresponding to a higher suicide risk. Low risk is 1–5 points, intermediate 6–9 points, and high risk ≥10 points. The suicide module of the Mini International Neuropsychiatric Interview (MINI) was recommended to screen PWE for suicidality (Hesdorffer Dale and Kanner Andres, 2009).
2. Methods
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2.3. Statistical analysis
Table 1 Demographic and clinical characteristics of the people with epilepsy(n = 276).
Statistical analysis was conducted using SPSS version 24.0 and PROCESS version 3.0 which is SPSS macros to facilitate estimation of both direct and the indirect effects (Preacher Kristopher and Hayes Andrew, 2004, 2008). Spearman’s correlation was used to assess the correlations between factors. The significance level was set at p < 0.05 (two-tailed). All continuous variables were mean-centered and the interaction terms were computed from these mean-centered scores. Mediation analysis was applied to examine whether depression mediates the relationship between seizure frequency and suicidal tendency. And then moderated mediation analysis was applied to examine whether the mediating associations were moderated by generalized anxiety (Hayes Andrew, 2015). For all mediation analysis, a bootstrapping approach (with 5000 bootstrap samples) was applied to obtaining bootstrap 95 % confidence interval (CI) to verify indirect effects. If the 95 % CI did not contain zero, then the indirect effect was determined to be statistically significant. 3. Results A total of 295 PWE were invited to participate in the current study. Among them, 11 PWE declined to participate. There were no significant differences in demographic and clinical features between patients who declined and patients who consented to participate (n = 284). Among these 284 patients, two had schizophrenia, and six scored less than 20 on the Mini-Mental State Examination (MMSE). Following exclusion of these patients, a total of 276 PWE completed the Mini-International Neuropsychiatric Interview and self-rating instruments with no items left blank. The demographic and clinical characteristics of the 276 participants in this study are shown in Table 1. 3.1. Preliminary analyses Means, standard deviations, and Spearman correlations for all study variables are presented in Table 2. As expected, seizure frequency was positively associated with depression severity, and depression severity was positively associated with suicidal tendency. Besides, PWE with higher generalized anxiety severity were more likely to have higher levels of suicidal tendency.
Characteristics
n
Age (years), mean ± SD Gender Male Female Domicile Urban area Rural area Marital status Single Married Education level Primary/Junior high school High school University and above Occupation Student Unemployed Employed Retired Age at onset (years), mean ± SD Years from seizure onset, mean ± SD Seizure frequency in the last 6 months No seizure (> 6months) < 1 time per month ≥1 time per month Epilepsy types Focal epilepsies Generalized epilepsies Unknown epilepsies AEDs therapy regimen Monotherapy oxcarbazepine sodium valproate lamotrigine topiramate levetiracetam carbamazepine phenobarbital Polytherapy(≥2AEDs)
33.29 ± 11.34
(%)
121 155
(56.2) (43.8)
202 74
(73.2) (26.8)
119 157
(43.1) (56.9)
70 81 125
(25.4) (29.3) (45.3)
36 66 155 19 21.32 ± 11.72 12.0 ± 9.50
(13.0) (23.9) (56.2) (6.9)
169 71 36
(61.2) (25.7) (13.0)
202 60 14
(73.2) (21.7) (5.1)
189 43 40 35 15 47 7 2 87
(68.5) (15.6) (14.5) (12.7) (5.4) (17.0) (2.5) (0.7) (31.5)
AEDs, antiepileptic drugs; SD, standard deviation.
p = 0.000). Fig. 2 illustrates the interaction between generalized anxiety severity and depression severity with suicidal tendency as a dependent variable in PWE. Depression severity and suicidal tendency were positively associated for PWE low in generalized anxiety severity (simple slope = 0.5699, SE = 0.2237, t = 2.5478, p = 0.011), and the association was stronger for PWE high in generalized anxiety severity (simple slope = 1.8630, SE = 0.1739,t = 10.7146,p = 0.000). The conditional indirect effect of seizure frequency on suicidal tendency was stronger for PWE high in generalized anxiety severity(B = 0.1331, SE = 0.0459, Bootstrap 95 % CI = 0.0428 to 0.2236)than for PWE low in generalized anxiety severity(B = 0.0407, SE = 0.0216, Bootstrap 95 % CI = 0.0057 to 0.0887).The index of moderated mediation was statistically different from zero (Index = 0.0507, SE = 0.0194, Bootstrap 95 % CI = 0.0161 to 0.0904). These results indicated that the indirect effect of seizure frequency on suicidal tendency through the mediation of depression severity was positively moderated by generalized anxiety severity. After adding generalized anxiety severity as moderator, the model significantly explained 42.7 % (R2, p = 0.000) of variance in suicidal tendency. The tested model and mean-centered path estimates are displayed in Fig. 3. Therefore, hypothesis 2 was supported.
3.2. Mediation analysis The parameter estimates for the total, direct and indirect effects with 95 % CI are shown in Table 3. The total effect of seizure frequency (B = 0.2010, SE = 0.0494, p = 0.000) on suicidal tendency was significant, and the model significantly explained 5.7 % (R2, p = 0.000) of variance in suicidal tendency. The mediation analysis confirmed that seizure frequency had an indirect effect on suicidal tendency through the mediating variable of depression severity in PWE (B = 0.1009, SE = 0.0355, Bootstrap95 % CI = 0.0338 to 0.1721). Depression severity partially mediated the relationship between seizure frequency and suicidal tendency. The indirect effects of seizure frequency on suicidal tendency through depression severity was positive, and accounted for 50.2 % of the total effects of seizure frequency on suicidal tendency. After adding depression severity as mediators, the model significantly explained 36.1 % (R2, p = 0.000) of variance in suicidal tendency. Thus, hypothesis 1 was supported. 3.3. Moderated mediation analysis
4. Discussion After identifying the indirect effect of depression severity on the relationship between seizure frequency and suicidal tendency, we investigated whether it was moderated by generalized anxiety severity. The interaction of depression severity and generalized anxiety severity had a significant effect on suicidal tendency (B = 0.7100, SE = 0.1302,
This current study examined the relationship between seizure frequency and suicidal tendency in PWE. We developed an integrated conceptual scheme, which proposed that the influence of the seizure frequency on suicidal tendency is more important than prior researches 3
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Table 2 Descriptive statistics and Spearman's correlations of the main study variables. Variables
1
2
3
4
1.Seizure frequency 2.Depression severity 3.Generalized anxiety severity 4.Suicidal tendency Mean ± SD
1 0.159** 0.208** 0.195** 2.93 ± 8.02
1 0.650** 0.572** 10.12 ± 3.63
1 0.398** 3.53 ± 4.29
1 1.50 ± 3.69
Note. N = 276. Seizure frequency = seizure frequency in the last 6 months. Depression severity = NDDI-E score. Generalized anxiety severity = GAD-7 score. Suicidal tendency = the score of suicidality module of MINI. SD: standard deviation. **p < 0.01.
has indicated(Lim et al., 2010；Hecimovic et al.,2012). A moderated mediation model was established to test whether depression severity would mediate the association between seizure frequency and suicidal tendency, and to test whether generalized anxiety severity would amplify the indirect effect of seizure frequency on suicidal tendency. Study results demonstrated that the influence of seizure frequency on suicidal tendency can be partially explained by the mediation of depression severity, and the magnitude of the indirect effect of seizure frequency on suicidal tendency was contingent upon generalized anxiety severity. This finding highlighted the important influence of generalized anxiety severity on suicidal tendency in PWE. Our study contributes to the literature by corroborating and supplementing prior researches in several ways. Prior studies have paid limited attention to the relationship between seizure frequency and suicidal tendency in PWE. To our knowledge, the present study is the first to investigate the mechanisms linking seizure frequency and suicidal tendency. We suggested that high seizure frequency might increase depression severity, which in turn would increase suicidal tendency. Hence, seizure frequency may play an indirect role in causing suicidal tendency. Therefore, high depression severity can be one of the explanatory mechanisms for why high seizure frequency was associated with higher probability of suicide (Park et al., 2015). This finding is important because it highlights the importance of reducing seizure frequency, which may be the basis of suicide prevention in PWE. Our findings also contribute to research on depression in PWE by investigating both antecedents and consequences of depression. Our findings are in line with previous studies that seizure frequency is an independent risk factor of depression (Kimiskidis Vasilios et al., 2007), and depression was an independent risk factor of suicide risk in PWE (Li et al., 2019). In view of the strong positive association between depression and suicidal tendency in PWE, depression is no doubt an important target in screening and intervention. Therefore, in clinical practice and research alike, most of the attention has been focused on depression rather than anxiety in PWE. In general population, the positive relationship of anxiety and suicidal tendency has been proved (Sareen et al., 2005；Wang et al., 2018). For the first time, our results provide evidence that the positive association between depression and suicidal tendency become stronger for PWE with higher generalized anxiety severity. We propose that reducing generalized anxiety severity
Fig. 2. Suicidal tendency as a function of depression severity and generalized anxiety severity. Functions are graphed for two levels of generalized anxiety severity(one standard deviation above the mean and one standard deviation below the mean).
help reduce the influence of depression on suicidal tendency in PWE. Several limitations of the current study should be acknowledged. At first, all participants were recruited from a single tertiary hospital, there may be a selection bias. Further multicenter studies are needed. Secondly, because our data were cross-sectional, further longitudinal research is needed to verify the direction of the correlations in our theoretical models. Third, our model significantly explained 42.7 % of variance in suicidal tendency, indicating that there might be other factors to be explored in future research. For example, it was reported that perceived stigma produced by mental or physical disorders may represent a significant risk factor for suicide (Carpiniello and Pinna, 2017). And a reduced quality of life (QOL) significantly increased the risk of suicide (Andrade-Machado et al., 2015). Finally, use of antiepileptic drugs may be associated with an increased risk of suicidal tendency and suicide in patients with epilepsy (Dreier Julie et al., 2019). Since all PWE in this study were taking one or more antiepileptic drugs, there may be bias due to the effect of different antiepileptic drugs on suicidal tendencies. Further studies are needed to verify our theoretical models in PWE receiving different antiepileptic drug monotherapies. In conclusion, the current study provides insight into a theoretical mechanism linking seizure frequency with suicidal tendency through depression in PWE. Our results suggested that reducing seizure
Table 3 Total, direct and indirect effect of seizure frequency on suicidal tendency. Effects on suicidal tendency
Total effect (c) Direct effect (c') Indirect effect
Variables
Seizure frequency Seizure frequency axb Seizure frequency(a) Depression severity(b)
B
SE
0.2010 0.1001 0.1009 0.0715 1.4122
0.0494 0.0416 0.0355 0.0200 0.1230
P
0.000 0.017 — 0.000 0.000
Bootstrap 95 % CI Lower
Upper
— — 0.0358 — —
— — 0.1721 — —
Note. Unstandardized regression coefficients are reported. Bold data show statistical significance(P < 0.05,or Bootstrap 95 % CI does not contain zero). 4
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Fig. 3. Moderated Mediation Model. Note.**p < 0.01.
frequency could be the basis of suicide prevention in PWE. At the same time, the effect of seizure frequency on suicidal tendency can be partially explained by the mediation of depression severity, and the magnitude of the indirect effect of seizure frequency on suicidal tendency was contingent upon generalized anxiety severity. In addition to depression severity, generalized anxiety severity also exerts an important effect on suicidal tendency in PWE.
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Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Effects of seizure frequency, depression and generalized anxiety on suicidal tendency in people with epilepsy
T
Xing Liu, Hongnian Chen, Zheng Xiao* Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, NO.1 Yixueyuan Rd. Yuzhong District, 400016, Chongqing, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Seizure frequency Depression Generalized anxiety Suicidal tendency Epilepsy
Purpose: The highest risk of suicide was identified among patients diagnosed with both epilepsy and comorbid psychiatric disease. The most common comorbid psychiatric conditions of epilepsy are anxiety and depression. This study examines whether and how seizure frequency, depression and generalized anxiety interact to influence suicidal tendency. Methods: A consecutive cohort of PWE was recruited from the First Affiliated Hospital of Chongqing Medical University. Each patient completed the Neurological Disorders Depression Inventory for Epilepsy scale[NDDI-E], the Generalized Anxiety Disorder-7 (GAD-7), and the suicidality module of Mini-International Neuropsychiatric Interview(MINI) v.5.0.0. Spearman’s correlation and moderated mediation analysis were used to examine the associations among seizure frequency, depression, generalized anxiety and suicidal tendency. Results: Seizure frequency was positively associated with suicidal tendency. Depression severity partially mediated the relationship between seizure frequency and suicidal tendency. The indirect effect of seizure frequency on suicidal tendency was positive, and accounted for 50.2 % of the total effect of seizure frequency on suicidal tendency. The indirect effect of seizure frequency on suicidal tendency through depression severity was positively moderated by generalized anxiety severity. Conclusions: Reducing seizure frequency may be the basis of suicide prevention in PWE. At the same time, the effect of seizure frequency on suicidal tendency can be partially explained by the mediation of depression severity, and the magnitude of the indirect effect of seizure frequency on suicidal tendency was contingent upon generalized anxiety severity. In addition to depression severity, generalized anxiety severity also exerts an important effect on suicidal tendency in PWE.
1. Introduction The prevalence of suicidal thoughts is 2–3 times higher in PWE than in those without epilepsy (Tellez-Zenteno Jose et al., 2007; Christensen et al., 2007). The highest risk of suicide was identified among patients diagnosed with both epilepsy and comorbid psychiatric disease (especially affective disorders) (Christensen et al., 2007). Moreover, the most common comorbid psychiatric conditions of epilepsy are major depression (17.4 %)and anxiety(22.8 %) (Tellez-Zenteno Jose et al., 2007). A recent cross-sectional study in China found that depression was an independent risk factor of suicide risk in PWE (Li et al., 2019). However, It was worrying that about 44 % of PWE reported they would not seek help when they were feeling stressed, worried, or low (Margrove Kerrie et al., 2011). In west China, the treatment gap of
depression in PWE was up to 72.5 % (Li et al., 2019). Therefore, it is taken for granted that more attention should be paid to comorbid depression in PWE. Besides, it is worthy of note that the current seizure frequency has significant associations with levels of depression (Jacoby et al.,1996). And high seizure frequency is an independent risk factor of depression (Kimiskidis Vasilios et al., 2007). One possible explanation may lay in that the learned helplessness due to the uncertainty and unpredictability of seizures, and the chronic stress exposure owing to the 'burden of epilepsy, might facilitate the development of depression (Hoppe and Elger Christian, 2011). Logically, we posit that seizure frequency will be positively associated with the severity of depression. And depression severity, in turn, will be positively associated with suicidal tendency. However prior studies reported that the major predictor of suicidal
Abbreviations: PWE, people with epilepsy; AEDs, antiepileptic drugs; NDDI-E, the neurological disorders depression inventory for epilepsy; GAD-7, the generalized anxiety disorder-7 ⁎ Corresponding author. E-mail address: [email protected] (X. Zheng). https://doi.org/10.1016/j.eplepsyres.2020.106265 Received 8 November 2019; Received in revised form 30 December 2019; Accepted 1 January 2020 Available online 03 January 2020 0920-1211/ © 2020 Elsevier B.V. All rights reserved.
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Fig. 1. illustration of proposed moderated-mediation conceptual model.
neurological/psychiatric disorders (eg, aphasia, schizophrenia) that could hamper accurate completion of the questionnaires.
ideation in PWE was depression rather than seizure-related variables (Lim et al., 2010；Hecimovic et al.,2012), therefore the relationship between seizure frequency and suicidal tendency deserves further research. On the other hand, a population-based longitudinal study found that comorbid anxiety disorders amplified the risk of suicide attempts in persons with mood disorders (Sareen et al., 2005). Coincidently, a recent study found that the co-occurrence of mood and anxiety disorders was the greatest risk factor of suicidal behaviors in general population (Wang et al., 2018). One reason may be that persons with anxiety disorder were at increased risk for deliberate self-harm, including suicide attempts (Chartrand et al., 2012). Therefore, we speculate that anxiety would interact with depression to increase suicidal tendency. Nevertheless, anxiety disorders in PWE have received far less attention than depression, and are ever called the “forgotten comorbidity” in PWE (Kanner Andres, 2011). Up to now, there have been few studies on how anxiety influences suicidal tendency in PWE. In the current study, we propose a conceptual model (see Fig.1)：(a)to test whether depression severity would mediate the association between seizure frequency and suicidal tendency, and(b)to test whether the indirect effect of seizure frequency on suicidal tendency through the mediation of depression severity would be moderated by generalized anxiety severity. Based on the literatures reviewed above, we propose the following hypotheses, H1：seizure frequency would increase depression severity, which in turn increases suicidal tendency. In other words, depression severity would mediate the association between seizure frequency and suicidal tendency；H2：Generalized anxiety severity would be positively associated with suicidal tendency. Furthermore, the positive relationship between depression severity and suicidal tendency would be stronger for PWE in high level of generalized anxiety severity than for PWE in low level of generalized anxiety severity.
2.2. Measures 2.2.1. The neurological disorders depression inventory for epilepsy (NDDIE) The NDDI-E is an epilepsy-specific self-rating questionnaire specifically developed to rapidly screen the symptoms of depression in the past two weeks in epilepsy clinic. It consists of six items reflecting depressive symptoms that can be differentiated from common side effects of AEDs (e.g., fatigue or experiencing cognitive problems) (Gilliam Frank et al., 2006). Each item is assigned a score of 1-4, which indicates 4 ranks from “never” to “always/often”. The total score ranges from 6 to 24, with a higher score corresponding to a higher depression severity. The NDDI-E has been validated in 13 languages (Gill Stephanie et al., 2017), including Chinese (Guo et al., 2015a, b; Tong et al., 2015). The validation studies of the NDDI-E have identified different cutoff scores for major depression, ranging from > 11 to > 16 (Kim et al., 2019).The NDDI-E was recommended to screen PWE for depression in International consensus clinical practice statements (Kerr Mike et al., 2011).
2.1. Participants
2.2.2. The generalized anxiety Disorder-7 (GAD-7) GAD-7 is a seven-item self-rating instrument developed to rapidly identify symptoms of generalized anxiety disorders in primary care sites. Its items describe the typical symptoms of general anxiety disorder (GAD) and rate on a 4-point scale, from “Not at all” to “Nearly every day”. A higher score represents higher anxiety severity. In the original study, a score of 10 or greater on the GAD-7 represents an optimal cut point for GAD (Spitzer Robert et al., 2006). It has been validated in patients with epilepsy in China, Korea and France, with a cut-off score of > 6 or > 7 for GAD (Tong et al., 2016; Seo et al., 2014; Micoulaud-Franchi et al., 2016). GAD-7 was one of the recommended instruments to screen PWE for anxiety (Hesdorffer Dale and Kanner Andres, 2009).
Participants were consecutively recruited from the epilepsy clinic of the First Affiliated Hospital of Chongqing Medical University, a large tertiary care hospital, from March to August 2019. The study protocol and consent forms were approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. Inclusion criteria were :(1)diagnosis of epilepsy according to the International League Against Epilepsy (ILAE) criteria (Fisher Robert et al., 2014). (2) age 18 years or older, (3) having received stable dose of one or more antiepileptic drugs for at least the past 30 days. (4) having received at least 6 years of education so that they have enough reading ability to complete the questionnaires. (5) willingness to provide written informed consent to participate the experimental procedures. Exclusion criteria were: (1) the Mini-Mental State Examination (MMSE) score is less than 20 for Participants being educated for 6 years, and less than 24 for those being educated for 7 or more years.(2) presence of significant
2.2.3. Mini-International neuropsychiatric interview (MINI) The MINI is brief, structured psychiatric diagnostic interviews compatible with the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV) and the International Classification of Diseases10(ICD-10)criteria. The MINI mainly explores DSM Axis I disorders and antisocial personality disorder(Sheehan et al.,1998).The suicide module of the MINI (Chinese version 5.0.0) focuses on current suicidal ideation and attempt in the past 4 weeks. It contains six questions, three of which are about suicide ideation, one about suicide plan, and two about suicide attempt within the past 4 weeks or in their lifetime. The total scores range from 0 to 33, with a higher score corresponding to a higher suicide risk. Low risk is 1–5 points, intermediate 6–9 points, and high risk ≥10 points. The suicide module of the Mini International Neuropsychiatric Interview (MINI) was recommended to screen PWE for suicidality (Hesdorffer Dale and Kanner Andres, 2009).
2. Methods
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2.3. Statistical analysis
Table 1 Demographic and clinical characteristics of the people with epilepsy(n = 276).
Statistical analysis was conducted using SPSS version 24.0 and PROCESS version 3.0 which is SPSS macros to facilitate estimation of both direct and the indirect effects (Preacher Kristopher and Hayes Andrew, 2004, 2008). Spearman’s correlation was used to assess the correlations between factors. The significance level was set at p < 0.05 (two-tailed). All continuous variables were mean-centered and the interaction terms were computed from these mean-centered scores. Mediation analysis was applied to examine whether depression mediates the relationship between seizure frequency and suicidal tendency. And then moderated mediation analysis was applied to examine whether the mediating associations were moderated by generalized anxiety (Hayes Andrew, 2015). For all mediation analysis, a bootstrapping approach (with 5000 bootstrap samples) was applied to obtaining bootstrap 95 % confidence interval (CI) to verify indirect effects. If the 95 % CI did not contain zero, then the indirect effect was determined to be statistically significant. 3. Results A total of 295 PWE were invited to participate in the current study. Among them, 11 PWE declined to participate. There were no significant differences in demographic and clinical features between patients who declined and patients who consented to participate (n = 284). Among these 284 patients, two had schizophrenia, and six scored less than 20 on the Mini-Mental State Examination (MMSE). Following exclusion of these patients, a total of 276 PWE completed the Mini-International Neuropsychiatric Interview and self-rating instruments with no items left blank. The demographic and clinical characteristics of the 276 participants in this study are shown in Table 1. 3.1. Preliminary analyses Means, standard deviations, and Spearman correlations for all study variables are presented in Table 2. As expected, seizure frequency was positively associated with depression severity, and depression severity was positively associated with suicidal tendency. Besides, PWE with higher generalized anxiety severity were more likely to have higher levels of suicidal tendency.
Characteristics
n
Age (years), mean ± SD Gender Male Female Domicile Urban area Rural area Marital status Single Married Education level Primary/Junior high school High school University and above Occupation Student Unemployed Employed Retired Age at onset (years), mean ± SD Years from seizure onset, mean ± SD Seizure frequency in the last 6 months No seizure (> 6months) < 1 time per month ≥1 time per month Epilepsy types Focal epilepsies Generalized epilepsies Unknown epilepsies AEDs therapy regimen Monotherapy oxcarbazepine sodium valproate lamotrigine topiramate levetiracetam carbamazepine phenobarbital Polytherapy(≥2AEDs)
33.29 ± 11.34
(%)
121 155
(56.2) (43.8)
202 74
(73.2) (26.8)
119 157
(43.1) (56.9)
70 81 125
(25.4) (29.3) (45.3)
36 66 155 19 21.32 ± 11.72 12.0 ± 9.50
(13.0) (23.9) (56.2) (6.9)
169 71 36
(61.2) (25.7) (13.0)
202 60 14
(73.2) (21.7) (5.1)
189 43 40 35 15 47 7 2 87
(68.5) (15.6) (14.5) (12.7) (5.4) (17.0) (2.5) (0.7) (31.5)
AEDs, antiepileptic drugs; SD, standard deviation.
p = 0.000). Fig. 2 illustrates the interaction between generalized anxiety severity and depression severity with suicidal tendency as a dependent variable in PWE. Depression severity and suicidal tendency were positively associated for PWE low in generalized anxiety severity (simple slope = 0.5699, SE = 0.2237, t = 2.5478, p = 0.011), and the association was stronger for PWE high in generalized anxiety severity (simple slope = 1.8630, SE = 0.1739,t = 10.7146,p = 0.000). The conditional indirect effect of seizure frequency on suicidal tendency was stronger for PWE high in generalized anxiety severity(B = 0.1331, SE = 0.0459, Bootstrap 95 % CI = 0.0428 to 0.2236)than for PWE low in generalized anxiety severity(B = 0.0407, SE = 0.0216, Bootstrap 95 % CI = 0.0057 to 0.0887).The index of moderated mediation was statistically different from zero (Index = 0.0507, SE = 0.0194, Bootstrap 95 % CI = 0.0161 to 0.0904). These results indicated that the indirect effect of seizure frequency on suicidal tendency through the mediation of depression severity was positively moderated by generalized anxiety severity. After adding generalized anxiety severity as moderator, the model significantly explained 42.7 % (R2, p = 0.000) of variance in suicidal tendency. The tested model and mean-centered path estimates are displayed in Fig. 3. Therefore, hypothesis 2 was supported.
3.2. Mediation analysis The parameter estimates for the total, direct and indirect effects with 95 % CI are shown in Table 3. The total effect of seizure frequency (B = 0.2010, SE = 0.0494, p = 0.000) on suicidal tendency was significant, and the model significantly explained 5.7 % (R2, p = 0.000) of variance in suicidal tendency. The mediation analysis confirmed that seizure frequency had an indirect effect on suicidal tendency through the mediating variable of depression severity in PWE (B = 0.1009, SE = 0.0355, Bootstrap95 % CI = 0.0338 to 0.1721). Depression severity partially mediated the relationship between seizure frequency and suicidal tendency. The indirect effects of seizure frequency on suicidal tendency through depression severity was positive, and accounted for 50.2 % of the total effects of seizure frequency on suicidal tendency. After adding depression severity as mediators, the model significantly explained 36.1 % (R2, p = 0.000) of variance in suicidal tendency. Thus, hypothesis 1 was supported. 3.3. Moderated mediation analysis
4. Discussion After identifying the indirect effect of depression severity on the relationship between seizure frequency and suicidal tendency, we investigated whether it was moderated by generalized anxiety severity. The interaction of depression severity and generalized anxiety severity had a significant effect on suicidal tendency (B = 0.7100, SE = 0.1302,
This current study examined the relationship between seizure frequency and suicidal tendency in PWE. We developed an integrated conceptual scheme, which proposed that the influence of the seizure frequency on suicidal tendency is more important than prior researches 3
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Table 2 Descriptive statistics and Spearman's correlations of the main study variables. Variables
1
2
3
4
1.Seizure frequency 2.Depression severity 3.Generalized anxiety severity 4.Suicidal tendency Mean ± SD
1 0.159** 0.208** 0.195** 2.93 ± 8.02
1 0.650** 0.572** 10.12 ± 3.63
1 0.398** 3.53 ± 4.29
1 1.50 ± 3.69
Note. N = 276. Seizure frequency = seizure frequency in the last 6 months. Depression severity = NDDI-E score. Generalized anxiety severity = GAD-7 score. Suicidal tendency = the score of suicidality module of MINI. SD: standard deviation. **p < 0.01.
has indicated(Lim et al., 2010；Hecimovic et al.,2012). A moderated mediation model was established to test whether depression severity would mediate the association between seizure frequency and suicidal tendency, and to test whether generalized anxiety severity would amplify the indirect effect of seizure frequency on suicidal tendency. Study results demonstrated that the influence of seizure frequency on suicidal tendency can be partially explained by the mediation of depression severity, and the magnitude of the indirect effect of seizure frequency on suicidal tendency was contingent upon generalized anxiety severity. This finding highlighted the important influence of generalized anxiety severity on suicidal tendency in PWE. Our study contributes to the literature by corroborating and supplementing prior researches in several ways. Prior studies have paid limited attention to the relationship between seizure frequency and suicidal tendency in PWE. To our knowledge, the present study is the first to investigate the mechanisms linking seizure frequency and suicidal tendency. We suggested that high seizure frequency might increase depression severity, which in turn would increase suicidal tendency. Hence, seizure frequency may play an indirect role in causing suicidal tendency. Therefore, high depression severity can be one of the explanatory mechanisms for why high seizure frequency was associated with higher probability of suicide (Park et al., 2015). This finding is important because it highlights the importance of reducing seizure frequency, which may be the basis of suicide prevention in PWE. Our findings also contribute to research on depression in PWE by investigating both antecedents and consequences of depression. Our findings are in line with previous studies that seizure frequency is an independent risk factor of depression (Kimiskidis Vasilios et al., 2007), and depression was an independent risk factor of suicide risk in PWE (Li et al., 2019). In view of the strong positive association between depression and suicidal tendency in PWE, depression is no doubt an important target in screening and intervention. Therefore, in clinical practice and research alike, most of the attention has been focused on depression rather than anxiety in PWE. In general population, the positive relationship of anxiety and suicidal tendency has been proved (Sareen et al., 2005；Wang et al., 2018). For the first time, our results provide evidence that the positive association between depression and suicidal tendency become stronger for PWE with higher generalized anxiety severity. We propose that reducing generalized anxiety severity
Fig. 2. Suicidal tendency as a function of depression severity and generalized anxiety severity. Functions are graphed for two levels of generalized anxiety severity(one standard deviation above the mean and one standard deviation below the mean).
help reduce the influence of depression on suicidal tendency in PWE. Several limitations of the current study should be acknowledged. At first, all participants were recruited from a single tertiary hospital, there may be a selection bias. Further multicenter studies are needed. Secondly, because our data were cross-sectional, further longitudinal research is needed to verify the direction of the correlations in our theoretical models. Third, our model significantly explained 42.7 % of variance in suicidal tendency, indicating that there might be other factors to be explored in future research. For example, it was reported that perceived stigma produced by mental or physical disorders may represent a significant risk factor for suicide (Carpiniello and Pinna, 2017). And a reduced quality of life (QOL) significantly increased the risk of suicide (Andrade-Machado et al., 2015). Finally, use of antiepileptic drugs may be associated with an increased risk of suicidal tendency and suicide in patients with epilepsy (Dreier Julie et al., 2019). Since all PWE in this study were taking one or more antiepileptic drugs, there may be bias due to the effect of different antiepileptic drugs on suicidal tendencies. Further studies are needed to verify our theoretical models in PWE receiving different antiepileptic drug monotherapies. In conclusion, the current study provides insight into a theoretical mechanism linking seizure frequency with suicidal tendency through depression in PWE. Our results suggested that reducing seizure
Table 3 Total, direct and indirect effect of seizure frequency on suicidal tendency. Effects on suicidal tendency
Total effect (c) Direct effect (c') Indirect effect
Variables
Seizure frequency Seizure frequency axb Seizure frequency(a) Depression severity(b)
B
SE
0.2010 0.1001 0.1009 0.0715 1.4122
0.0494 0.0416 0.0355 0.0200 0.1230
P
0.000 0.017 — 0.000 0.000
Bootstrap 95 % CI Lower
Upper
— — 0.0358 — —
— — 0.1721 — —
Note. Unstandardized regression coefficients are reported. Bold data show statistical significance(P < 0.05,or Bootstrap 95 % CI does not contain zero). 4
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Fig. 3. Moderated Mediation Model. Note.**p < 0.01.
frequency could be the basis of suicide prevention in PWE. At the same time, the effect of seizure frequency on suicidal tendency can be partially explained by the mediation of depression severity, and the magnitude of the indirect effect of seizure frequency on suicidal tendency was contingent upon generalized anxiety severity. In addition to depression severity, generalized anxiety severity also exerts an important effect on suicidal tendency in PWE.
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5. Declaration of Competing Interest None. Authors’ contributions Xin Liu analyzed the data and drafted the manuscript for intellectual content. Hongnian Chen contributed to the acquisition of data. Zheng Xiao, MD designed the study and revised the manuscript for intellectual content. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements We would like to thank Yi Bao from West China hospital for her advice in statistics. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.eplepsyres.2020. 106265. References Andrade-Machado, Rene, Ochoa-Urrea, Manuela, Garcia-Espinosa, Arlety, et al., 2015. Suicidal risk, affective dysphoric disorders, and quality-of-life perception in patients with focal refractory epilepsy. Epilepsy Behav 45, 254–260. Carpiniello, Bernardo, Pinna, Federica, 2017. The reciprocal relationship between suicidality and stigma. Front. Psychiatry 8, 35. Christensen, Jakob, Vestergaard, Mogens, Mortensen Preben, Bo, Sidenius, Per, Agerbo, Esben, 2007. Epilepsy and risk of suicide: a population-based case-control study. Lancet Neurol. 6, 693–698. Chartrand, Hayley, Sareen, Jitender, Toews, Matthew, Bolton James, M., 2012. Suicide attempts versus nonsuicidal self-injury among individuals with anxiety disorders in a nationally representative sample. Depress. Anxiety 29, 172–179. Dreier Julie, W., Pedersen Carsten, B., Christiane, Gasse, Jakob, Christensen, 2019. Antiepileptic drugs and suicide: role of Prior suicidal behavior and parental psychiatric disorder. Ann. Neurol. 86, 951–961. Fisher Robert, S., Carlos, Acevedo, Alexis, Arzimanoglou, Alicia, Bogacz, Helen, Cross J., Elger Christian, E., Jerome, Engel, Lars, Forsgren, French Jacqueline, A., Mike, Glynn, Hesdorffer Dale, C., Lee, B.I., Mathern Gary, W., Moshé Solomon, L., Perucca, Emilio., Scheffer Ingrid, E., Torbjörn, Tomson, Masako, Watanabe, Samuel, Wiebe, 2014.
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