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Psychiatric symptoms predict drug-resistant epilepsy in newly treated patients

Published:October 23, 2022DOI:https://doi.org/10.1016/j.seizure.2022.10.019

      Highlights

      • Of the 217 patients, 17.5% had depressive symptoms, and 31.3% had anxiety symptoms at baseline. DRE was diagnosed in 26.7% of patients (n=58).
      • Risk factor for the development of DRE included history of brain trauma, >5 seizures pretreatment, multiple seizure type, brain MRI lesion, depressive and anxiety symptoms.
      • The HRs of developing DRE was 5.219 times higher in patients with both depressive and anxiety symptoms than that in patients without depressive or anxiety symptoms.

      Abstract

      Purpose

      Literature on the complex interrelationships between psychiatric symptoms and drug resistance in newly treated patients with epilepsy (PWE) is lacking. We aimed to determine whether psychiatric symptoms are predictive of the development of drug-resistant epilepsy (DRE) in newly treated patients.

      Methods

      Newly treated PWE were psychiatrically evaluated at enrolment and were followed for 24 months to determine the occurrence of DRE. The impacts of depressive and anxiety symptoms on the development of DRE were investigated using the Cox proportional hazard model.

      Results

      A total of 217 patients were included in the final analysis. DRE was diagnosed in 26.7% of patients (n=58). In univariate analysis, depressive and anxiety symptoms were identified as risk factors for the development of DRE. In multivariate analyses, depressive symptoms were a significant independent predictor of DRE (HR: 3.253, 95% CI: 1.643-6.441; p = 0.001). Additionally, the probability of developing DRE was 5.219 times higher in patients with both depressive and anxiety symptoms than in patients without depressive or anxiety symptoms (HR: 5.219, 95% CI: 2.716-10.029; p<0.001).

      Conclusion

      In conclusion, psychiatric symptoms provide prognostic information regarding the occurrence of DRE in patients newly treated with ASMs. Our findings support the need for prospective studies to investigate whether psychiatric treatment reduces the risk of developing DRE in these patients.

      Keywords

      1. Introduction

      Epilepsy is one of the most common serious neurological disorders, affecting over 70 million people worldwide [
      • Thijs RD
      • Surges R
      • O'Brien TJ
      • Sander JW.
      Epilepsy in adults.
      ]. Approximately 30% to 40% of patients with epilepsy (PWE) develop drug-resistant epilepsy (DRE) despite receiving appropriate anti-seizure medication (ASM)[
      • Kwan P
      • Brodie MJ.
      Early identification of refractory epilepsy.
      ,
      • Panayiotopoulos CP.
      Old versus new antiepileptic drugs: the SANAD study.
      ]. It is well documented that drug-resistant epilepsy is associated with an increased risk of mortality, injuries, psychosocial dysfunction, and poor quality of life [
      • Mohanraj R
      • Norrie J
      • Stephen LJ
      • Kelly K
      • Hitiris N
      • Brodie MJ
      Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study.
      ,
      • Lawn ND
      • Bamlet WR
      • Radhakrishnan K
      • O'Brien PC
      • So EL
      Injuries due to seizures in persons with epilepsy: a population-based study.
      ,
      • McCagh J
      • Fisk JE
      • Baker GA.
      Epilepsy, psychosocial and cognitive functioning.
      ,
      • Kwan P
      • Schachter SC
      • Brodie MJ.
      Drug-resistant epilepsy.
      ]. Thus, identifying clinically useful predictors of the occurrence of DRE in newly treated patients would have significant clinical benefits. Predictors of DRE vary widely across prior literature, ranging from early age at onset, abnormal neuroimaging, symptomatic epilepsy, and seizure type [
      • Choi H
      • Detyniecki K
      • Bazil C
      • et al.
      Development and validation of a predictive model of drug-resistant genetic generalized epilepsy.
      ,
      • Kong ST
      • Ho CS
      • Ho PC
      • Lim SH.
      Prevalence of drug resistant epilepsy in adults with epilepsy attending a neurology clinic of a tertiary referral hospital in Singapore.
      ,
      • Casetta I
      • Granieri E
      • Monetti VC
      • et al.
      Early predictors of intractability in childhood epilepsy: a community-based case-control study in Copparo, Italy.
      ,
      • Gilioli I
      • Vignoli A
      • Visani E
      • et al.
      Focal epilepsies in adult patients attending two epilepsy centers: classification of drug-resistance, assessment of risk factors, and usefulness of "new" antiepileptic drugs.
      ].
      Psychiatric comorbidities are common in PWE [
      • Kanner AM.
      Management of psychiatric and neurological comorbidities in epilepsy.
      ,
      • Berg AT
      • Altalib HH
      • Devinsky O.
      Psychiatric and behavioral comorbidities in epilepsy: A critical reappraisal.
      ]. Psychiatric comorbidities could negatively influence quality of life and increase the risk of morbidity and premature mortality in PWE [
      • Ogundare T
      • Adebowale TO
      • Borba C
      • Henderson DC.
      Correlates of depression and quality of life among patients with epilepsy in Nigeria.
      ,
      • Mula M
      • Sander JW.
      Current and emerging drug therapies for the treatment of depression in adults with epilepsy.
      ,
      • Siarava E
      • Hyphantis T
      • Katsanos AH
      • Pelidou SH
      • Kyritsis AP
      • Markoula S.
      Depression and quality of life in patients with epilepsy in Northwest Greece.
      ]. Increasing evidence has confirmed the pathophysiologic link between epilepsy and psychiatric disorders [
      • Hesdorffer DC
      • Hauser WA
      • Olafsson E
      • Ludvigsson P
      • Kjartansson O.
      Depression and suicide attempt as risk factors for incident unprovoked seizures.
      ,
      • Forsgren L.
      Prospective incidence study and clinical characterization of seizures in newly referred adults.
      ]. Psychological stress may determine changes in brain structure and function [
      • McEwen BS
      • Gianaros PJ.
      Stress- and allostasis-induced brain plasticity.
      ,
      • McEwen BS.
      Brain on stress: how the social environment gets under the skin.
      ], increase seizure susceptibility [
      • Salzberg M
      • Kumar G
      • Supit L
      • et al.
      Early postnatal stress confers enduring vulnerability to limbic epileptogenesis.
      ], and promote pharmacoresistant seizures [
      • Kanner AM
      • Byrne R
      • Chicharro A
      • Wuu J
      • Frey M.
      A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy.
      ]. In a population-based case‒control study, a history of major depression was found to increase the risk for unprovoked seizure and the development of epilepsy [
      • Hesdorffer DC
      • Hauser WA
      • Olafsson E
      • Ludvigsson P
      • Kjartansson O.
      Depression and suicide attempt as risk factors for incident unprovoked seizures.
      ]. Neuropsychiatric symptomatology could predict the high likelihood of seizure recurrence in patients newly treated with ASMs [
      • Petrovski S
      • Szoeke CE
      • Jones NC
      • et al.
      Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients.
      ].
      Until now, however, evidence on the association between psychiatric symptoms at baseline and the development of DRE in newly treated patients has been limited. This study aimed to test our hypothesis that psychiatric symptoms are predictive of the occurrence of DRE in patients newly treated with ASMs.

      2. Methods

      2.1 Study design and participants

      The prospective cohort study was performed at the Epilepsy Center, Neurology Department of Jilin University, First Hospital between June 2016 and May 2021. Newly treated PWE aged 18 years or older were invited to participate in our study [
      • Scheffer IE
      • Berkovic S
      • Capovilla G
      • et al.
      ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.
      ,
      • Fisher RS
      • Cross JH
      • French JA
      • et al.
      Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.
      ]. Psychiatric symptoms of each participant were evaluated before they received ASM therapy. Patients were prospectively followed up for 24 months to evaluate the occurrence of DRE. The exclusion criteria consisted of 1) previously treated with ASM therapy; 2) a history of psychiatric disorders (lifelong anxiety and depression); and 3) a history of nonepileptic seizures and severe brain diseases other than epilepsy (e.g., dementia and Parkinson's disease). These medical histories were identified by reviewing the medical records and patient self-reports. We also excluded subjects who did not have the physical, mental, and language ability to complete the self-report questionnaires and interview. Written informed consent was obtained from all participants. This study was reviewed and approved by the ethics committee of our hospital.

      2.2 Psychiatric evaluation

      Psychiatric evaluation was performed before starting ASM treatment. The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E, Chinese version) [
      • Gilliam FG
      • Barry JJ
      • Hermann BP
      • Meador KJ
      • Vahle V
      • Kanner AM.
      Rapid detection of major depression in epilepsy: a multicentre study.
      ] and the Generalized Anxiety Disorder-7 questionnaire (GAD-7, Chinese Version) [
      • Spitzer RL
      • Kroenke K
      • Williams JB
      • Lowe B.
      A brief measure for assessing generalized anxiety disorder: the GAD-7.
      ] were used. The NDDI-E was employed to screen the comorbidity of depressive symptoms in PWE [
      • Gilliam FG
      • Barry JJ
      • Hermann BP
      • Meador KJ
      • Vahle V
      • Kanner AM.
      Rapid detection of major depression in epilepsy: a multicentre study.
      ]. The GAD-7 is a rapid and user-friendly clinical instrument for screening anxiety symptoms [
      • Spitzer RL
      • Kroenke K
      • Williams JB
      • Lowe B.
      A brief measure for assessing generalized anxiety disorder: the GAD-7.
      ]. These questionnaires have been validated in Chinese PWE [
      • Tong X
      • An D
      • McGonigal A
      • Park SP
      • Zhou D.
      Validation of the Generalized Anxiety Disorder-7 (GAD-7) among Chinese people with epilepsy.
      ,
      • Tong X
      • An D
      • Lan L
      • et al.
      Validation of the Chinese version of the Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E) in West China.
      ]. A score greater than 12 on the NDDI-E indicates depressive symptoms, and a score of >6 on the GAD-7 indicates anxiety symptoms in patients [
      • Tong X
      • An D
      • McGonigal A
      • Park SP
      • Zhou D.
      Validation of the Generalized Anxiety Disorder-7 (GAD-7) among Chinese people with epilepsy.
      ,
      • Tong X
      • An D
      • Lan L
      • et al.
      Validation of the Chinese version of the Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E) in West China.
      ].

      2.3 Follow-up and outcome variables

      Participants were interviewed via clinical visit and/or telephone at 1, 3, and 6 months after enrolment and every 6 months thereafter. Additionally, patients were requested to contact their treating physician within days of experiencing a breakthrough seizure. At each follow-up, information on seizure recurrence, medication compliance and changes, and potential adverse effects was collected. The outcome variable was a binary variable of the occurrence of DRE during a 24-month follow-up period. The definition of DRE according to the ILEA is failure of adequate trials of two tolerated, appropriately chosen and used ASM schedules (including monotherapies or combination therapies) to achieve sustained seizure freedom [
      • Kwan P
      • Arzimanoglou A
      • Berg AT
      • et al.
      Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.
      ]. Participants were classified as “DRE cases” or “ASMs - responsive controls” according to whether they developed DRE.

      2.4 Potential predictors

      Eighteen variables were considered potential predictors of DRE based on the literature and clinical reasoning, and information on these variable was gathered at enrolment. Of these 18 potential predictors, 16 were binary variables: sex, employed, per capita monthly family income, age at onset (divided into binary: > 45 and ≤ 45 years), family history of epilepsy in a first-degree relative, febrile seizures, history of encephalitis, history of brain trauma, history of stroke, >50% nocturnal seizures, > 5 seizures pretreatment, symptomatic epilepsy, multiple seizure types, status epilepticus (SE), and brain MRI lesions. Here, >50% nocturnal seizures was defined as >50% of seizures occurring during sleep, including daytime naps. SE was defined if the diagnostic time exceeded 5 minutes of ongoing seizure activity for convulsive SE or 10 minutes for absence status or focal status with or without impaired consciousness [
      • Trinka E
      • Cock H
      • Hesdorffer D
      • et al.
      A definition and classification of status epilepticus–Report of the ILAE Task Force on Classification of Status Epilepticus.
      ]. Brain MRI scans were performed to confirm the presence of a structural lesion. Seizure type was divided into 3 categories: focal, generalized, and unknown.

      2.5 Statistical analysis

      Categorical variables are summarized as frequencies and percentages. Variables were compared using chi-squared tests, and Fisher's exact tests were employed if X2 assumptions were not met. A Cox proportional hazard model was used to identify the effect of each parameter on the occurrence of DRE and to calculate the hazard ratio (HR). Variables with p < 0.05 in the univariate analysis were subsequently included in the multivariate analysis to identify the independent predictors of DRE. The follow-up times for the occurrence of DRE were calculated using the Kaplan‒Meier method. Then, we examined the associations of psychiatric symptoms at baseline with the development of DRE using a Cox proportional hazard model that controlled for potential confounders. We measured model performance using Nagelkerke's R2 statistics. All data analyses were performed using SPSS for Windows, version 26.0 (SPSS Inc., Chicago, IL, USA). The level of statistical significance was set at 0.05 (two-sided).

      3. Results

      Of the 283 potentially eligible patients identified, 66 were ineligible based on the following reasons: not interested in participating in the study (n = 7), treated with ASM previously (n = 5), withdrew from the study (n = 13), never started or ceased ASM treatment (n = 19), and lost to follow-up (n = 22). A total of 217 patients were included in the final analysis. Table 1 presents the demographic, clinical and psychiatric data of the patient cohort. Of the 217 patients, 17.5% had depressive symptoms, and 31.3% had anxiety symptoms at baseline. DRE was diagnosed in 26.7% of patients (n=58) during the follow-up.
      Table 1Baseline characteristics of DRE cases and controls.
      Predictor variablesDRE cases (n=58)Controls (n=159)p-valueTotal cases (n=217)
      Gender
       Male30 (51.7)99 (62.3)0.162129 (59.4)
       Female28 (31.8)60 (68.2)
      Employed41 (70.7)120 (75.5)0.476161 (74.2)
      Per capita monthly family income (Yuan)
       < 10003 (5.2)19 (11.9)0.32422 (10.1)
       1000-500044 (75.9)109 (68.6)153 (70.5)
       > 500011 (19.0)31 (19.5)42 (19.4)
      Age at onset, years
       ≤4547 (81.0)107 (67.3)0.048154 (71.0)
       >4511 (19.0)52 (32.7)63 (29.0)
      Family history of epilepsy8 (13.8)12 (7.5)0.15920 (9.2)
      Febrile seizures5 (8.6)14 (8.8)0.96619 (8.8)
      History of encephalitis4 (6.9)8 (5.0)0.84412 (5.5)
      History of brain trauma14 (24.1)17 (10.7)0.01231 (14.3)
      History of stroke4 (6.9)9 (5.7)0.99513 (6.0)
      >50% nocturnal seizures34 (58.6)90 (56.6)0.79124 (57.1)
      Seizure type
       Generalized10 (17.2)27 (17.0)0.84237 (17.1)
       Focal44 (75.9)117 (73.6)161 (74.2)
       Unknown4 (6.9)15 (9.4)19 (8.8)
      > 5 seizures pretreatment39 (67.2)63 (39.6)< 0.001102 (47.0)
      Symptomatic epilepsy21 (36.2)36 (22.6)0.04457 (26.3)
      Multiple seizure types32 (55.2)43 (27.0)< 0.00175 (34.6)
      Status epilepticus8 (13.8)13 (8.2)0.21621 (9.7)
      Brain MRI lesion33 (56.9)42 (26.4)< 0.00175 (34.6)
      Anxiety symptoms34 (58.6)34 (21.4)< 0.00168 (31.3)
      Depressive symptoms26 (44.8)12 (7.5)< 0.00138 (17.5)
      DRE, drug-resistant epilepsy; MRI, magnetic resonance imaging.
      Bold entries indicate p < 0.05.
      The baseline characteristics of DRE cases and controls are compared in Table 1. Significant differences in history of brain trauma, age at onset, > 5 seizures pretreatment, and brain MRI lesions were noted between DRE cases and controls. The proportions of symptomatic epilepsy and multiple seizure types were higher among DRE cases than controls. Depressive and anxiety symptoms at baseline were both more common in DRE cases (p<0.001). No significant differences in other variables were observed between the DRE cases and controls (p>0.05).
      In univariate analysis, risk factors for the development of DRE included history of brain trauma, >5 seizures pretreatment, multiple seizure type, and brain MRI lesion (Table 2). The HRs were also high for age at onset and for symptomatic epilepsy, but they were not statistically significant. Depressive symptoms (HR: 6.046, 95% CI: 3.583-10.2; p<0.001, Fig. 1 A) and anxiety symptoms (HR: 4.083, 95% CI: 2.416-6.899; p<0.001, Fig. 1 B) were associated with increased HRs of drug resistance. No other factor was associated with the HRs for DRE.
      Table 2Univariate analysis showing the predictors of DRE.
      Predictive variablesCrude HR95% CIp-value
      Gender
       Male0.6820.407 - 1.1410.145
       FemaleRef
      Employed
       Yes0.8420.479 - 1.4830.552
       NoRef
      Per capita monthly family income (Yuan)
       < 10000.520.145 - 1.8650.316
       1000-50001.1420.59 - 2.2120.693
       > 5000Ref
      Age at onset, years
       ≤451.8820.976 - 3.630.059
       >45Ref
      Family history of epilepsy
       Yes1.4820.702 - 3.1270.302
       NoRef
      Febrile seizures
       Yes0.9670.386 - 2.4180.942
       NoRef
      >50% nocturnal seizures
       Yes1.0640.631 - 1.7950.815
       NoRef
      History of encephalitis
       Yes1.2250.444 - 3.3840.695
       NoRef
      History of brain trauma
       Yes2.2641.24 - 4.1330.008
       NoRef
      History of stroke
       Yes1.1270.408 - 3.1130.817
       NoRef
      Seizure type
       Focal1.3760.494 - 3.8290.541
       Generalized1.3580.426 - 4.3290.605
       unknownRef
      > 5 seizures pretreatment
       Yes2.7011.56 - 4.676<0.001
       NoRef
      Symptomatic epilepsy
       Yes1.6680.976 - 2.8490.061
       NoRef
      Multiple seizure types
       Yes2.681.596 - 4.5<0.001
       NoRef
      Status epilepticus
       Yes1.6520.783 - 3.4840.188
       NoRef
      Brain MRI lesion
       Yes2.9431.748 - 4.953<0.001
       NoRef
      Anxiety symptoms
       Yes4.0832.416 - 6.899<0.001
       NoRef
      Depressive symptoms
       Yes6.0463.583 - 10.2<0.001
       NoRef
      DRE, drug-resistant epilepsy; MRI, magnetic resonance imaging; HR, hazard ratio; 95% CI, confidence interval.
      Bold entries indicate p < 0.05.
      Fig. 1
      Fig. 1Kaplan‒Meier curve shows that patients with depressive symptoms (A) and anxiety symptoms (B) had an increased risk of DRE.
      DRE, drug-resistant epilepsy.
      A univariate analysis was performed for preliminary identification of factors related to drug resistance. A history of brain trauma, >5 seizures pretreatment, multiple seizure type, brain MRI lesion, depressive and anxiety symptoms were identified at a significance level of p < 0.05 (Table 2) and were retained for the multivariate analysis. Multivariate analysis suggested that the HRs of patients with depressive symptoms developing DRE were 3.253 times greater than those of patients without these symptoms (HR: 3.253, 95% CI: 1.643-6.6441; p = 0.001) (Table 3). In addition, >5 seizures pretreatment and brain MRI lesions were also significant independent predictors of DRE. The model explained 38.9% (Nagelkerke's R2) of the variance.
      Table 3Multivariate analysis showing the independent predictors of DRE.
      Predictive variablesAdjusted HR95% CIp-value
      History of brain trauma
      Yes1.6020.869 - 2.9520.131
      NoRef
      > 5 seizures pretreatment
       Yes2.0961.181 - 3.7220.012
       NoRef
      Multiple seizure types
       Yes1.4710.833 - 2.5990.184
       NoRef
      Brain MRI lesion
       Yes2.2081.272 - 3.8340.003
       NoRef
      Anxiety symptoms
       Yes1.6710.827 - 3.3760.152
       NoRef
      Depressive symptoms
       Yes3.2531.643 - 6.4410.001
       NoRef
      DRE, drug-resistant epilepsy; MRI, magnetic resonance imaging; HR, hazard ratio; 95% CI, confidence interval.
      Bold entries indicate p < 0.05.
      Table 4 and Fig. 2 show the incidence rate of DRE and the HRs for occurrence of DRE according to psychiatric symptoms. The lowest incidence rate of DRE (15.2%) was observed in patients without depressive or anxiety symptoms. The highest incidence rate of DRE (69.2%) was noted in patients with both depressive and anxiety symptoms. Multivariate analysis suggested that the HRs of developing DRE were 5.219 times higher in patients with both depressive and anxiety symptoms than in patients without depressive or anxiety symptoms (HR: 5.219, 95% CI: 2.716-10.029; p<0.001).
      Table 4Associations of psychiatric symptoms with the risk of DRE.
      Incidence rate of DRE (%)Univariate analysisMultivariate analysis
      Crude HR95% CIAdjusted HR95% CI
      Group A15.2%RefRef
      Group B36.6%2.7631.432 - 5.33
      p<0.01
      2.2871.161 -4.508
      p<0.05
      Group C60.0%5.0831.52 - 16.997
      p<0.01
      5.3161.546 -18.283
      p<0.01
      Group D69.2%7.7654.14 - 14.565
      p<0.001.
      5.2192.716 - 10.029
      p<0.001.
      DRE, drug-resistant epilepsy; MRI, magnetic resonance imaging; HR, hazard ratio; 95% CI, confidence interval.
      Group A: patients without depressive or anxiety symptoms;
      Group B: patients with only anxiety symptoms;
      Group C: patients with only depressive symptoms;
      Group D: patients with both depressive and anxiety symptoms;
      low asterisk p<0.05
      low asterisklow asterisk p<0.01
      low asterisklow asterisklow asterisk p<0.001.
      Fig. 2
      Fig. 2Bar graph of the incidence rate of DRE according to psychiatric symptoms.
      DRE, drug-resistant epilepsy.
      Group A: patients without depressive or anxiety symptoms;
      Group B: patients with only anxiety symptoms;
      Group C: patients with only depressive symptoms;
      Group D: patients with both depressive and anxiety symptoms;

      4. Discussion

      This is the first study to follow a representative cohort of adults with newly diagnosed epilepsy to determine whether psychiatric symptoms at baseline are predictive of a high likelihood of developing DRE. We found that psychiatric symptoms provide prognostic information regarding the occurrence of DRE in patients newly treated with ASMs. To some extent, our findings are consistent with prior literature showing that a history of psychiatric conditions is an important predictor of ASM resistance in PWE [
      • Choi H
      • Detyniecki K
      • Bazil C
      • et al.
      Development and validation of a predictive model of drug-resistant genetic generalized epilepsy.
      ].
      It has been reported that the prevalence of DRE ranges from 11% to 58% in PWE [
      • Kalilani L
      • Sun X
      • Pelgrims B
      • Noack-Rink M
      • Villanueva V.
      The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis.
      ]. The wide variation in the definition of DRE among the studies may lead to significant heterogeneity in the prevalence. Most prior studies on the topic of DRE were performed before the publication of the ILAE definition of DRE in 2010 [
      • Kwan P
      • Arzimanoglou A
      • Berg AT
      • et al.
      Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.
      ,
      • Hitiris N
      • Mohanraj R
      • Norrie J
      • Sills GJ
      • Brodie MJ
      Predictors of pharmacoresistant epilepsy.
      ,
      • Aikia M
      • Kalviainen R
      • Mervaala E
      • Riekkinen PS.
      Predictors of seizure outcome in newly diagnosed partial epilepsy: memory performance as a prognostic factor.
      ]. A total of 26.7% of adults with epilepsy developed DRE in our cohort, which was slightly lower than the pooled prevalence of 30% reported by Kalilani et al. [
      • Kalilani L
      • Sun X
      • Pelgrims B
      • Noack-Rink M
      • Villanueva V.
      The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis.
      ]. One explanation may be the relatively short follow-up period, which may lead to an underestimation of the incidence rate of DRE. Another possible explanation could be that some patients at high risk of developing DRE were not included in our study based on the exclusion criteria.
      Our results suggested that psychiatric symptoms at baseline were predictive of the development of DRE in patients newly treated with ASMs. The predictive value of depressive and anxiety symptoms with respect to DRE is significant. In this study, the NDDI-E and GAD-7 are rapid and user-friendly clinical questionnaires used to evaluate the severity of depressive and anxiety symptoms, respectively, which have been validated in Chinese PWE [
      • Tong X
      • An D
      • Lan L
      • et al.
      Validation of the Chinese version of the Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E) in West China.
      ,
      • Tong X
      • An D
      • McGonigal A
      • Park SP
      • Zhou D.
      Validation of the Generalized Anxiety Disorder-7 (GAD-7) among Chinese people with epilepsy.
      ]. These two questionnaires could be completed by a patient in approximately 2-3 minutes, making it a practical tool for routine clinical use.
      Abundant evidence indicates the bidirectional association between epilepsy and psychiatric conditions [
      • Hesdorffer DC
      • Ishihara L
      • Mynepalli L
      • Webb DJ
      • Weil J
      • Hauser WA.
      Epilepsy, suicidality, and psychiatric disorders: a bidirectional association.
      ,
      • Josephson CB
      • Lowerison M
      • Vallerand I
      • et al.
      Association of Depression and Treated Depression With Epilepsy and Seizure Outcomes: A Multicohort Analysis.
      ]. Prior literature suggested that the first occurrences of depression and anxiety were significantly increased both before and after epilepsy diagnosis [
      • Hesdorffer DC
      • Ishihara L
      • Mynepalli L
      • Webb DJ
      • Weil J
      • Hauser WA.
      Epilepsy, suicidality, and psychiatric disorders: a bidirectional association.
      ]. It is well known that the burden of an epilepsy diagnosis and the long-term use of ASMs may lead to psychiatric disorders. Depression and anxiety trajectories were predicted by the patient's sense of loss of seizure control early after epilepsy diagnosis, and the use of ASMs was related to increased levels of distress [
      • Velissaris SL
      • Saling MM
      • Newton MR
      • Berkovic SF
      • Wilson SJ.
      Psychological trajectories in the year after a newly diagnosed seizure.
      ]. The impacts of psychiatric conditions on epilepsy have also been widely investigated. A history of depression is associated with an increased risk of developing epilepsy [
      • Hesdorffer DC
      • Hauser WA
      • Olafsson E
      • Ludvigsson P
      • Kjartansson O.
      Depression and suicide attempt as risk factors for incident unprovoked seizures.
      ] and a worse prognosis of epilepsy [
      • Hitiris N
      • Mohanraj R
      • Norrie J
      • Sills GJ
      • Brodie MJ
      Predictors of pharmacoresistant epilepsy.
      ]. A lifetime psychiatric history is predictive of a worse postsurgical seizure outcome after an anterotemporal lobectomy [
      • Kanner AM
      • Byrne R
      • Chicharro A
      • Wuu J
      • Frey M.
      A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy.
      ]. Neuropsychiatric symptomatology predicts the failure of seizure control in patients newly treated with ASMs [
      • Petrovski S
      • Szoeke CE
      • Jones NC
      • et al.
      Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients.
      ]. Furthermore, treated depression is related to worse seizure outcomes in PWE, indicating that the severity of depression is associated with the severity of epilepsy [
      • Josephson CB
      • Lowerison M
      • Vallerand I
      • et al.
      Association of Depression and Treated Depression With Epilepsy and Seizure Outcomes: A Multicohort Analysis.
      ]. Supportive evidence for the negative effect of depression on seizure control is also found in a recent randomized trial for the treatment of depression in epilepsy, in which significantly fewer seizures occurred in patients who achieved remission for depression [
      • Gilliam FG
      • Black KJ
      • Carter J
      • et al.
      A Trial of Sertraline or Cognitive Behavior Therapy for Depression in Epilepsy.
      ].
      The biological explanation for the relationship we have confirmed between the emerging psychiatric symptoms and the occurrence of DRE in newly treated patients remains unclear. Common pathogenic mechanisms potentially exist in psychiatric conditions and epilepsy [
      • Jobe PC
      • Dailey JW
      • Wernicke JF.
      A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders.
      ,
      • Kanner AM.
      Depression in epilepsy: a neurobiologic perspective.
      ]. Abnormalities in serotonergic and noradrenergic transmission are vital pathogenic mechanisms of psychiatric disorders that could also facilitate the kindling process of seizure foci, exacerbate seizure severity, and intensify seizure predisposition [
      • Kanner AM.
      Depression in epilepsy: a neurobiologic perspective.
      ,
      • Nemeroff CB
      • Owens MJ.
      Treatment of mood disorders.
      ]. Structural and functional abnormalities of the same neuroanatomic regions may be involved in the pathogenic mechanisms of psychiatric disorders and epileptic disorders [
      • Kanner AM.
      Depression in epilepsy: a neurobiologic perspective.
      ,
      • Kanner AM.
      Mood disorder and epilepsy: a neurobiologic perspective of their relationship.
      ]. Evidence indicates a relationship between the extent of hippocampal dysfunction with the severity of depression symptoms in epilepsy [
      • Gilliam FG
      • Maton BM
      • Martin RC
      • et al.
      Hippocampal 1H-MRSI correlates with severity of depression symptoms in temporal lobe epilepsy.
      ]. Hippocampal sclerosis has also been reported to be one of the major pathogenic factors of DRE [
      • Sendrowski K
      • Sobaniec W.
      Hippocampus, hippocampal sclerosis and epilepsy.
      ]. Additionally, cognitive function in major depression disorders may be related to aberrant functional connectivity in cognitive networks, and patterns of alternate brain networks could influence cognitive processes [
      • Albert KM
      • Potter GG
      • Boyd BD
      • Kang H
      • Taylor WD.
      Brain network functional connectivity and cognitive performance in major depressive disorder.
      ]. Individuals with Alzheimer's disease have an increased risk for seizures [
      • Voglein J
      • Ricard I
      • Noachtar S
      • et al.
      Seizures in Alzheimer's disease are highly recurrent and associated with a poor disease course.
      ].
      Several limitations should be noted in the present study. First, depressive and anxiety symptoms were diagnosed according to the scores of the C-NDDI-E and GAD-7 scales in this study, which have been widely used in Mainland China [
      • Wang HJ
      • Tan G
      • Deng Y
      • et al.
      Prevalence and risk factors of depression and anxiety among patients with convulsive epilepsy in rural West China.
      ,
      • Zhong R
      • Chen Q
      • Li M
      • et al.
      Factors contributing to comorbid depressive symptoms in adult people with newly diagnosed epilepsy: A 12-month longitudinal study.
      ]. However, clinical diagnosis is clearly the gold standard. These scales were not substitutes for clinical interviews or the Diagnostic and Statistical Manual (4th ed.) diagnosis. Second, data on counselling or psychological treatments were not available. Thus, this variable could not be included as a possible confounder. The impacts of psychological treatments on the development of DRE require more investigation. Third, it was not possible to collect all potential risk factors for DRE, and the possibility of residual confounding remains. Finally, we cannot provide an independent sample, and our model lacks confirmation in an independent sample. We also did not report sensitivity, specificity or predictive values.
      In conclusion, psychiatric symptoms provide prognostic information regarding the occurrence of DRE in patients newly treated with ASMs. Well-designed and statistically powered studies are required to confirm our findings. Furthermore, our findings might inform prospective studies investigating whether psychiatric treatment reduces the risk of developing DRE in patients newly treated with ASMs.

      Author contributions statement

      WL and RZ conceived of and designed the study. RZ, XZ, and NL were involved in data acquisition. QC and RJ analysed the data and wrote the manuscript. All authors contributed to the article and approved the submitted version.

      Data Availability Statement

      The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

      Declaration of Competing Interest

      The authors of this work have nothing to disclose.

      Acknowledgements

      The authors would like to thank all of the participants for their valuable information, cooperation, and participation.

      Funding

      This work was supported by funds from the Clinical Research Development Fund of The First Hospital of Jilin University (grant number: lcpyjj2017006).

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