Epilepsy & Behavior 33 (2014) 106–109
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Determinants of depression among patients with epilepsy in Athens, Greece Panagiotis Zis a,⁎, Paraskevi Yfanti a, Anna Siatouni b, Antonios Tavernarakis a, Stylianos Gatzonis b a b
Department of Neurology, Evangelismos Hospital, Athens, Greece Department of Neurosurgery, University of Athens, Evangelismos General Hospital, Athens, Greece
a r t i c l e
i n f o
Article history: Received 5 December 2013 Revised 25 January 2014 Accepted 22 February 2014 Available online 18 March 2014 Keywords: Depression Epilepsy Determinants Unemployment
a b s t r a c t Objective: Depression is common among patients with epilepsy. The aim of our study was twofold: to estimate the prevalence of a major depressive episode and to identify its determinants among patients with epilepsy treated in the largest Greek hospital in Athens. Methods: All consecutive patients with epilepsy that visited the epilepsy outpatient clinic of Evangelismos General Hospital were invited to participate in the study. Ninety-four patients met our inclusion criteria. Results: A diagnosis of a current major depressive episode was established in 21 out of 94 eligible to participate (22.3%) patients. Being a female was associated with a 19.68-fold increase in the odds of having a major depressive episode (95% CI 3.39–114.14, p = 0.001); being unemployed was associated with a 6.46-fold increase in the odds of having a major depressive episode (95% CI 1.23–34.07, p = 0.028), and each extra seizure experienced per month was associated with a 1.38-fold increase in the odds of having a major depressive episode (95% CI 1.03–1.85, p = 0.031). Conclusion: Unemployment, female gender, and seizure control are important determinants of a major depression episode among patients with epilepsy. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Psychiatric disorders are common among patients with epilepsy. Extensive research has been conducted to study the coexistence of neuropsychiatric symptoms with epilepsy [1]. The prevalence of a current depressive episode in patients with epilepsy ranges from 11% to 62% [2] and represents the most common psychiatric comorbidity in epilepsy [3]. The variance in the frequency of depression may stem from the use of differing patient samples. Regardless of this fact, depression in epilepsy is a pervasive problem and frequently goes unrecognized and untreated [4]. Often, depression is viewed as a reaction to epilepsy's stigma and the associated poor quality of life. However, the manifestation of depression in epilepsy is multifaceted with many interacting neurobiological and psychosocial determinants, including clinical features of epilepsy (seizure frequency, type, foci, or lateralization of foci) and neurochemical or iatrogenic mechanisms [5]. Moreover, treatment with antiepileptic drugs (AEDs) and social coping and adaptation skills have also been identified as risk factors of depression associated with epilepsy [6]. Until now, depression in patients with epilepsy in Greece has not been adequately studied. In a previous study, Kimiskidis et al. investigated the association of interictal mood disorders with various ⁎ Corresponding author at: Evangelismos General Hospital, Department of Neurology, 45-47 Ipsilantou Str, 10676 Athens, Greece. Tel.: +30 697 410446; fax: +30 213 2041403. E-mail address: [email protected] (P. Zis).
http://dx.doi.org/10.1016/j.yebeh.2014.02.024 1525-5050/© 2014 Elsevier Inc. All rights reserved.
demographic and seizure-related variables in patients with newly diagnosed and chronic epilepsy. The authors concluded that female gender, high seizure frequency, and a symptomatic epilepsy syndrome are independent risk factors for the development of anxiety and/or depression [7]. The aims of our study were twofold: to estimate the prevalence of a major depressive episode and to identify its determinants among patients with epilepsy treated in the largest Greek hospital in Athens. 2. Methods 2.1. Participants All consecutive patients with epilepsy that visited the epilepsy outpatient clinic of Evangelismos General Hospital were invited to participate in the study. To be enrolled, the patients had to meet the following inclusion criteria: (1) confirmed diagnosis of any type of epilepsy according to the International League Against Epilepsy (ILAE) criteria [8,9], documented clinically and confirmed with the EEG studies; (2) age equal to or greater than 18 years; (3) no gross cognitive deficits or intellectual disability; (4) absence of life threatening or severely disabling medical diseases (i.e., cancer, stroke, etc.); (5) a native Greek speaker; and (6) willing to provide a written informed consent to undergo the experimental procedures.
P. Zis et al. / Epilepsy & Behavior 33 (2014) 106–109
2.2. Psychiatric evaluation All subjects were assessed using the following instruments on the same visit. 2.2.1. Mini International Neuropsychiatric Interview (MINI — Greek version 5.0.0.) The MINI is an internationally validated, brief structured interview that has been used extensively as a diagnostic tool for Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV) and International Classification of Diseases-10 (ICD-10) psychiatric disorders. The reliability and validity of this instrument have been established [10]. The MINI was administered by the same investigator (PY) to all patients. 2.2.2. Psychiatric interview A detailed psychiatric assessment was completed by the main investigator (PZ) to diagnose if the patient was currently experiencing a major depressive episode. The DSM-IV criteria for a major depressive episode were used [11]. 2.3. Statistical analyses A database was developed using the Statistical Package for Social Science (version 16.0 for Mac; SPSS). Frequencies and descriptive statistics were examined for each variable. Comparisons between patients with a current major depressive episode and patients without a current major depressive episode were made using Student's t-tests for normally distributed continuous data, Mann-Whitney's U test for non-normally distributed data, and chi-square test for categorical data. Where statistically significant differences were found, correlations were carried out to identify variables that could be entered into a logistic regression model to identify determinants of depression among the patients with epilepsy. Where variables were correlated, the most clinically relevant was selected for inclusion in the model. The variables were entered as independent variables, and current major depressive episode was entered as the dependent variable. A value of p b 0.05 was considered to be statistically significant. 3. Results Between February 2013 and July 2013, 97 individuals fulfilled the abovementioned inclusion criteria. Out of them, 3 patients did not have an identical diagnosis according to the MINI questionnaire and the psychiatric interview. Therefore, our final study population consisted of 94 patients. A diagnosis of a current major depressive episode was established in 21 (22.3%) patients. The severity of the episode was evaluated to be mild in 10 patients (47.6% of the subgroup with current major depressive episode), moderate in 4 patients (19.0%), and severe in 7 patients (33.3%). In total, 13 patients of the subgroup (61.9%) had active suicidal ideation, but no patients had made any attempt to commit suicide. Table 1 summarizes the AEDs used and their corresponding psychotropic effects on depression as reported in the literature. The most widely used antiepileptic drug was levetiracetam (29.8%), followed by sodium valproate (28.7%), carbamazepine (24.5%), and oxcarbazepine (24.5%). Clinical and demographic characteristics of the study's total population and the two subgroups (depressed and nondepressed patients) are shown in Table 2. Regarding the clinical characteristics, the depressed patients were more likely to be females, had fewer years of education, and were more likely to be unemployed. Regarding the epilepsyrelated characteristics, the depressed patients had a longer history of epilepsy, were experiencing seizures more frequently, were receiving more AEDs, and were more likely to receive AEDs with negative psychotropic effects. There were no other statistically significant differences
107
Table 1 Antiepileptic agents used in our study group, and their correspondent psychotropic effects [34,35] regarding depression. Antiepileptic drug
Number
Percentage
Psychotropic effects [34,35]
Levetiracetam Sodium valproate Carbamazepine Oxcarbazepine Topiramate Benzodiazepines Lacosamide Lamotrigine Pregabalin Phenytoin Primidone Phenobarbital Zonisamide
28 27 23 23 22 15 12 9 8 7 6 6 4
29.8% 28.7% 24.5% 24.5% 23.4% 16.0% 12.8% 9.6% 8.5% 7.4% 6.4% 6.4% 4.3%
Negative Neutral Neutral Neutral Negative Negative Limited experience Positive Negative Neutral Negative Negative Negative
regarding the clinical and demographic characteristics between the two groups. The following independent variables were entered into the multivariate logistic regression model: age, sex, education years, employment status (being unemployed or not), duration of epilepsy, seizure frequency, number of AEDs, and type of AEDs (negative psychotropic effect or not). The results of the multivariate logistic regression are shown in Table 3. Adjusted odds ratios are presented. The full model significantly predicted a major depressive episode (χ2 = 37.95, df = 8, p b 0.001) with the majority of the variance (34 to 52%) being explained by three variables: gender, employment status, and seizure frequency. Being a female was associated with a 19.68-fold increase in the odds of having a major depressive episode (95% CI 3.39–114.14, p = 0.001); being unemployed was associated with a 6.46-fold increase in the odds of having a major depressive episode (95% CI 1.23–34.07, p = 0.028), and each extra seizure experienced per month was associated with a 1.38-fold increase in the odds of having a major depressive episode (95% CI 1.03–1.85, p = 0.031). 4. Discussion Our cross-sectional study has estimated that the prevalence of a major depressive episode among the patients with epilepsy treated in the largest Greek hospital in Athens is 22.3%. Moreover, we showed that female gender, unemployment, and increased seizure frequency are factors associated with a major depressive episode. The novelty of our study is that this is the first Greek study that aimed to investigate the prevalence of a major depressive episode and to identify its determinants among patients with epilepsy. Apart from its epidemiological importance for Greece, our study was conducted in an era of a severe financial crisis, which has already led to a dramatic increase of unemployment in the general population. The effects of unemployment on mental health are well described [12]. Depression tends to be more common among the long-term unemployed [13]. In 2011, in the beginning of the crisis, Economou et al. showed that the prevalence of major depression in the general population of Greece had already increased by almost 3 times, jumping from 3.3% to 8.2% [14]. This has also led to a substantial increase in the prevalence of suicidal ideation and reported suicide attempts [15]. Patients with epilepsy may have difficulty in finding and maintaining regular employment. They face appropriate restrictions, such as those relating to driving or working in situations in which they might be liable to injury. They may also be the victims of ignorance and stigma [16]. Additionally, a clear relationship between current seizure frequency and employment status has been demonstrated [17]. However, in our study, we showed that unemployment is independently associated with a major depressive episode after having adjusted for seizure frequency. Seizure frequency has been associated with psychological disturbances in a number of studies. Dias et al. concluded that major
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P. Zis et al. / Epilepsy & Behavior 33 (2014) 106–109
Table 2 Demographic and clinical characteristics of study total population and subgroups.
Demographic characteristics Female sex (%) Age, in years (SD) Marital status (%) Single Married Divorced Widowed Education years (SD) Employment status (%) Homemaker Full-time student Employed part-time Employed full-time Retired Unemployed Epilepsy-related characteristics Duration of epilepsy, in years (SD) Number of seizures per month (SD) Seizure type (%) Simple partial Complex partial Partial evolving to secondary general Absence Myoclonic Tonic–clonic Atonic Number of AEDs (SD) Receiving AEDs with negative psychotropic effects (%)
Total (n = 94)
Depressed (n = 21)
Nondepressed (n = 73)
p
45 (47.9) 36.8 (13.2)
16 (76.2) 34.7 (11.9)
29 (39.7) 37.3 (13.6)
0.003** 0.425
57 (60.6) 31 (33.0) 5 (5.3) 1 (1.1) 12.7 (3.3)
13 (61.8) 6 (28.6) 1 (4.8) 1 (4.8) 11.2 (2.8)
44 (60.3) 25 (34.2) 4 (5.5) 0 (0.0) 13.0 (3.4)
11 (11.7) 15 (16.0) 8 (8.5) 32 (34.0) 11 (11.7) 17 (18.1)
5 (23.8) 3 (14.3) 2 (9.5) 2 (9.5) 2 (9.5) 7 (33.4)
6 (8.2) 12 (16.4) 6 (8.2) 30 (41.1) 9 (12.4) 10 (13.7)
16.6 (13.1) 1.8 (2.9)
21.7 (11.6) 3.6 (4.3)
15.2 (13.2) 1.3 (2.2)
12 (12.8) 49 (52.1) 18 (19.1) 3 (3.2) 1 (1.1) 10 (10.6) 1 (1.1) 2.0 (1.1) 55 (58.5)
0 (0.0) 14 (66.6) 6 (28.6) 0 (0.0) 0 (0.0) 1 (4.8) 0 (0.0) 2.6 (1.1) 38 (52.1)
12 (16.4) 35 (47.9) 12 (16.4) 3 (4.1) 1 (1.4) 9 (12.4) 1 (1.4) 1.8 (1.0) 17 (81.0)
0.301
0.040*
0.037*
0.048* 0.002**
0.230
0.004** 0.018*
* p b 0.05, ** p b 0.01
depression is associated with uncontrolled seizures, with prevalence double that of patients whose seizures are controlled [18]. In a community-based survey, Jacoby et al. [17] observed that 21% of patients with recurrent seizures were depressed versus 9% of patients with controlled seizures, and O'Donoghue et al. [19] have similarly demonstrated at primary care settings that 33% of patients with recurrent seizures versus 6% of those in remission had probable depression. Overall, the prevalence of depression has been reported to range from 20 to 55% in populations with seizures that are resistant to treatment versus 3–9% in subjects with well-controlled seizures [20]. In an interesting study, aiming to test a theoretical explanatory model of the relationship between depression symptom scores and seizure frequency in people with epilepsy, Thapar et al. concluded that the relationship between depression symptom scores and seizure frequency in those with epilepsy is bidirectional [21]. Our study estimated that each extra reported seizure per month is associated with a 38% increase in the odds of experiencing a major depressive episode. In other words, better seizure control protects patients with epilepsy from depression. However, the occurrence of depression, particularly in patients with high seizure frequency, might seem paradoxical as one of the most powerful treatments for depression is electroconvulsive therapy, which is entirely based on the tenet of the antidepressive effects of convulsions [7].
The effect of gender on the development of psychiatric disturbances in epilepsy has been highly controversial in previous studies, most likely due to diverse methodological approaches and differences in the investigated populations [7,22–27]. Our study has shown that female gender increases the odds of having a major depressive episode. This is consistent with the fact that in the general population, women are more likely than men to suffer from depression; therefore, female gender could be considered a major risk factor for developing this condition also among patients with epilepsy [28]. Moreover, there is a growing body of research that suggests that men are less likely than women to seek help from health professionals [29], which has also been shown in the Greek population [30]. Therefore, the percentage of male patients with epilepsy suffering from a major depressive episode might have been underestimated, especially since there is a higher chance of men having missed their appointments if depressed. Our results should be interpreted with some caution given the limitations of our design. Firstly, although the determinants of depression in our study population are in agreement with those in other studies, the effect of female gender was related to an exceedingly high increase in the odds of having a major depressive episode, a finding that is not supported by other studies. Apart from the fact that this may be explained by the idiosyncrasy of Greek men and their tendency not to seek help
Table 3 Patient characteristics investigated for their association with a major depressive episode. Variable
ORa (95% CI)
Wald
p-Value
Age (per year) Female sex Education (per year) Being unemployed Duration of epilepsy (per year) Monthly frequency (per seizure) Number of AEDs (per extra agent) Receiving AEDs with potentially negative psychotropic effects
0.966 (0.907–1.038) 19.683 (3.394–114.138) 0.882 (0.711–1.094) 6.460 (1.225–34.069) 1.066 (0.992–1.145) 1.381 (1.029–1.853) 0.944 (0.426–2.095) 3.445 (0.675–17.590)
0.894 11.041 1.311 4.837 3.037 4.631 0.020 2.210
0.344 0.001 0.252 0.028 0.081 0.031 0.888 0.137
a
Adjusted odd ratios (OR) presented.
P. Zis et al. / Epilepsy & Behavior 33 (2014) 106–109
when needed, the corresponding confidence intervals of the adjusted odds ratios were ranging widely. This possibly could be explained by our relatively small sample size. Secondly, although we were recording all severely disabling or life-threatening medical comorbidities, such as cancer and stroke, we did not include in our analysis less severe medical comorbidities. Adjusting for such comorbidities is of particular interest, but it also requires a much greater sample size. Despite the fact that our study population included patients of all age groups, education levels, and different types of epilepsy, we had few patients with myoclonic, atonic, and absence seizures. This might have been the reason for not finding statistically significant correlations between seizure type and depression. Moreover, although the diagnosis of epilepsy was based on the ILAE criteria and on documented EEG reports, we could not include in our analysis specific electroclinical findings but only clinically documented seizure type. Finally, our cohort comprised users of one clinical service, and results may not be generalizable to other settings. Diagnosing depression requires psychiatric evaluation; however, useful clinician-rated questionnaires, such as the MINI [10], self-rated generic questionnaires, such as Hamilton Anxiety and Depression Scale [31], or self-rated disease-specific questionnaires, such as the Neurological Disorders Depression Inventory for Epilepsy [32,33], can be used to identify patients experiencing a major depressive episode and, consequently, treat them appropriately. In our study, we used only clinician-rated measures. However, self-completed instruments might offer a useful complement to capture the patient's own report, even in primary care settings. Living in an era of a severe financial crisis, which affects many countries worldwide, clinicians, not only epilepsy specialists, should be aware of the fact that depression is common in patients with epilepsy. Unemployment rates are expected to grow within the next years; therefore, our finding that unemployment is independently associated with depression among patients with epilepsy is especially important. Acknowledgments We are sincerely thankful to the patients who participated in the study. Conflict of interest None. References [1] Seidenberg M, Pulsipher DT, Hermann B. Association of epilepsy and comorbid conditions. Future Neurol 2009;4(5):663–8. [2] Barry JJ, Huynh N, Lembke A. Depression in individuals with epilepsy. Curr Treat Options Neurol 2000;2(6):571–85. [3] LaFrance Jr WC, Kanner AM, Hermann B. Psychiatric comorbidities in epilepsy. Int Rev Neurobiol 2008;83:347–83. [4] Hermann BP, Seidenberg M, Bell B. Psychiatric comorbidity in chronic epilepsy: identification, consequences, and treatment of major depression. Epilepsia 2000;41(Suppl. 2):S31–41. [5] Harden CL. The co-morbidity of depression and epilepsy: epidemiology, etiology, and treatment. Neurology 2002;59(6 Suppl. 4):S48–55. [6] Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004;110(4):207–20. [7] Kimiskidis VK, Triantafyllou NI, Kararizou E, Gatzonis SS, Fountoulakis KN, Siatouni A, et al. Depression and anxiety in epilepsy: the association with demographic and seizure-related variables. Ann Gen Psychiatry 2007;6:28.
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[8] Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. [9] Commission on Classification and Terminology of the International League against Epilepsy. Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 1985;26:268–78. [10] Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The MiniInternational Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(Suppl. 20):22–33 [quiz 34–57]. [11] American Psychiatric Association, editor. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR®. American Psychiatric Pub; 2000. [12] Rodriguez E, Frongillo EA, Chandra P. Do social programmes contribute to mental well-being? The long-term impact of unemployment on depression in the United States. Int J Epidemiol 2001;30(1):163–70. [13] Stankunas M, Kalediene R, Starkuviene S, Kapustinskiene V. Duration of unemployment and depression: a cross-sectional survey in Lithuania. BMC Public Health 2006;6:174. [14] Economou M, Madianos M, Peppou LE, Patelakis A, Stefanis CN. Major depression in the era of economic crisis: a replication of a cross-sectional study across Greece. J Affect Disord 2013;145(3):308–14. [15] Economou M, Madianos M, Peppou LE, Theleritis C, Patelakis A, Stefanis C. Suicidal ideation and reported suicide attempts in Greece during the economic crisis. World Psychiatry 2013;12(1):53–9. [16] Gloag D. Epilepsy and employment. Br Med J (Clin Res Ed) 1985;291(6487):2–3. [17] Jacoby A, Baker GA, Steen N, Potts P, Chadwick DW. The clinical course of epilepsy and its psychosocial correlates: finding from a U.K. community study. Epilepsia 1996;37:148–61. [18] Dias R, Bateman LM, Farias ST, Li CS, Lin TC, Jorgensen J, et al. Depression in epilepsy is associated with lack of seizure control. Epilepsy Behav 2010;19(3):445–7. [19] O'Donoghue MF, Goodridge DM, Redhead K, Sander JW, Duncan JS. Assessing the psychosocial consequences of epilepsy: a community-based study. Br J Gen Pract 1999;49:211–4. [20] Gilliam FG, Santos J, Vahle V, Carter J, Brown K, Hecimovic H. Depression in epilepsy: ignoring clinical expression of neuronal network dysfunction? Epilepsia 2004;45:28–34. [21] Thapar A, Roland M, Harold G. Do depression symptoms predict seizure frequency— or vice versa? J Psychosom Res 2005;59(5):269–74. [22] Mendez MF, Cummings JL, Benson DF. Depression in epilepsy. Significance and phenomenology. Arch Neurol 1986;43:766–70. [23] Kogeorgos J, Fonagy P, Scott DF. Psychiatric symptom patterns of chronic epileptics attending a neurological clinic: a controlled investigation. Br J Psychiatry 1982;140: 236–43. [24] Septien L, Grass P, Giroud M, Didi-Roy R, Brunotte F, Pelletier JL, et al. Depression and temporal lobe epilepsy: the possible role of laterality of the epileptic foci and gender. Neurophysiol Clin 1993;23:327–36. http://dx.doi.org/10.1016/S0987-7053(05) 80124-8. [25] Standage KF, Fenton GW. Psychiatric symptom profiles of patients with epilepsy: a controlled investigation. Psychol Med 1973;5:152–60. [26] Victoroff JI, Benson DF, Engel Jr J, Grafton S, Mazziotta JC. Interictal depression in patients with medically intractable complex partial seizures: electroencephalography and cerebral metabolic correlates. Ann Neurol 1990;28:221. [27] Robertson MM, Channon S, Baker J. Depressive symptomatology in a general hospital sample of outpatients with temporal lobe epilepsy: a controlled study. Epilepsia 1994;35:771–7. [28] Cavanna AE, Cavanna S, Bertero L, Robertson MM. Depression in women with epilepsy: clinical and neurobiological aspects. Funct Neurol 2009;24(2):83–7. [29] Galdas PM, Cheater F, Marshall P. Men and health help-seeking behaviour: literature review. J Adv Nurs 2005;49(6):616–23. [30] Madianos MG, Zartaloudi A, Alevizopoulos G, Katostaras T. Attitudes toward helpseeking and duration of untreated mental disorders in a sectorized Athens area of Greece. Community Ment Health J 2011;47(5):583–93. [31] Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67(6):361–70. [32] Gilliam FG, Barry JJ, Hermann BP, Meador KJ, Vahle V, Kanner AM. Rapid detection of major depression in epilepsy: a multicentre study. Lancet Neurol 2006;5(5):399–405. [33] Zis P, Yfanti P, Siatouni A, Tavernarakis A, Gatzonis S. Validation of the Greek version of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Epilepsy Behav 2013;29(3):513–5. [34] Perucca P, Mula M. Antiepileptic drug effects on mood and behavior: molecular targets. Epilepsy Behav 2013;26(3):440–9. [35] Nadkarni S, Devinsky O. Psychotropic effects of antiepileptic drugs. Epilepsy Curr 2005;5(5):176–81.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Determinants of depression among patients with epilepsy in Athens, Greece Panagiotis Zis a,⁎, Paraskevi Yfanti a, Anna Siatouni b, Antonios Tavernarakis a, Stylianos Gatzonis b a b
Department of Neurology, Evangelismos Hospital, Athens, Greece Department of Neurosurgery, University of Athens, Evangelismos General Hospital, Athens, Greece
a r t i c l e
i n f o
Article history: Received 5 December 2013 Revised 25 January 2014 Accepted 22 February 2014 Available online 18 March 2014 Keywords: Depression Epilepsy Determinants Unemployment
a b s t r a c t Objective: Depression is common among patients with epilepsy. The aim of our study was twofold: to estimate the prevalence of a major depressive episode and to identify its determinants among patients with epilepsy treated in the largest Greek hospital in Athens. Methods: All consecutive patients with epilepsy that visited the epilepsy outpatient clinic of Evangelismos General Hospital were invited to participate in the study. Ninety-four patients met our inclusion criteria. Results: A diagnosis of a current major depressive episode was established in 21 out of 94 eligible to participate (22.3%) patients. Being a female was associated with a 19.68-fold increase in the odds of having a major depressive episode (95% CI 3.39–114.14, p = 0.001); being unemployed was associated with a 6.46-fold increase in the odds of having a major depressive episode (95% CI 1.23–34.07, p = 0.028), and each extra seizure experienced per month was associated with a 1.38-fold increase in the odds of having a major depressive episode (95% CI 1.03–1.85, p = 0.031). Conclusion: Unemployment, female gender, and seizure control are important determinants of a major depression episode among patients with epilepsy. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Psychiatric disorders are common among patients with epilepsy. Extensive research has been conducted to study the coexistence of neuropsychiatric symptoms with epilepsy [1]. The prevalence of a current depressive episode in patients with epilepsy ranges from 11% to 62% [2] and represents the most common psychiatric comorbidity in epilepsy [3]. The variance in the frequency of depression may stem from the use of differing patient samples. Regardless of this fact, depression in epilepsy is a pervasive problem and frequently goes unrecognized and untreated [4]. Often, depression is viewed as a reaction to epilepsy's stigma and the associated poor quality of life. However, the manifestation of depression in epilepsy is multifaceted with many interacting neurobiological and psychosocial determinants, including clinical features of epilepsy (seizure frequency, type, foci, or lateralization of foci) and neurochemical or iatrogenic mechanisms [5]. Moreover, treatment with antiepileptic drugs (AEDs) and social coping and adaptation skills have also been identified as risk factors of depression associated with epilepsy [6]. Until now, depression in patients with epilepsy in Greece has not been adequately studied. In a previous study, Kimiskidis et al. investigated the association of interictal mood disorders with various ⁎ Corresponding author at: Evangelismos General Hospital, Department of Neurology, 45-47 Ipsilantou Str, 10676 Athens, Greece. Tel.: +30 697 410446; fax: +30 213 2041403. E-mail address: [email protected] (P. Zis).
http://dx.doi.org/10.1016/j.yebeh.2014.02.024 1525-5050/© 2014 Elsevier Inc. All rights reserved.
demographic and seizure-related variables in patients with newly diagnosed and chronic epilepsy. The authors concluded that female gender, high seizure frequency, and a symptomatic epilepsy syndrome are independent risk factors for the development of anxiety and/or depression [7]. The aims of our study were twofold: to estimate the prevalence of a major depressive episode and to identify its determinants among patients with epilepsy treated in the largest Greek hospital in Athens. 2. Methods 2.1. Participants All consecutive patients with epilepsy that visited the epilepsy outpatient clinic of Evangelismos General Hospital were invited to participate in the study. To be enrolled, the patients had to meet the following inclusion criteria: (1) confirmed diagnosis of any type of epilepsy according to the International League Against Epilepsy (ILAE) criteria [8,9], documented clinically and confirmed with the EEG studies; (2) age equal to or greater than 18 years; (3) no gross cognitive deficits or intellectual disability; (4) absence of life threatening or severely disabling medical diseases (i.e., cancer, stroke, etc.); (5) a native Greek speaker; and (6) willing to provide a written informed consent to undergo the experimental procedures.
P. Zis et al. / Epilepsy & Behavior 33 (2014) 106–109
2.2. Psychiatric evaluation All subjects were assessed using the following instruments on the same visit. 2.2.1. Mini International Neuropsychiatric Interview (MINI — Greek version 5.0.0.) The MINI is an internationally validated, brief structured interview that has been used extensively as a diagnostic tool for Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV) and International Classification of Diseases-10 (ICD-10) psychiatric disorders. The reliability and validity of this instrument have been established [10]. The MINI was administered by the same investigator (PY) to all patients. 2.2.2. Psychiatric interview A detailed psychiatric assessment was completed by the main investigator (PZ) to diagnose if the patient was currently experiencing a major depressive episode. The DSM-IV criteria for a major depressive episode were used [11]. 2.3. Statistical analyses A database was developed using the Statistical Package for Social Science (version 16.0 for Mac; SPSS). Frequencies and descriptive statistics were examined for each variable. Comparisons between patients with a current major depressive episode and patients without a current major depressive episode were made using Student's t-tests for normally distributed continuous data, Mann-Whitney's U test for non-normally distributed data, and chi-square test for categorical data. Where statistically significant differences were found, correlations were carried out to identify variables that could be entered into a logistic regression model to identify determinants of depression among the patients with epilepsy. Where variables were correlated, the most clinically relevant was selected for inclusion in the model. The variables were entered as independent variables, and current major depressive episode was entered as the dependent variable. A value of p b 0.05 was considered to be statistically significant. 3. Results Between February 2013 and July 2013, 97 individuals fulfilled the abovementioned inclusion criteria. Out of them, 3 patients did not have an identical diagnosis according to the MINI questionnaire and the psychiatric interview. Therefore, our final study population consisted of 94 patients. A diagnosis of a current major depressive episode was established in 21 (22.3%) patients. The severity of the episode was evaluated to be mild in 10 patients (47.6% of the subgroup with current major depressive episode), moderate in 4 patients (19.0%), and severe in 7 patients (33.3%). In total, 13 patients of the subgroup (61.9%) had active suicidal ideation, but no patients had made any attempt to commit suicide. Table 1 summarizes the AEDs used and their corresponding psychotropic effects on depression as reported in the literature. The most widely used antiepileptic drug was levetiracetam (29.8%), followed by sodium valproate (28.7%), carbamazepine (24.5%), and oxcarbazepine (24.5%). Clinical and demographic characteristics of the study's total population and the two subgroups (depressed and nondepressed patients) are shown in Table 2. Regarding the clinical characteristics, the depressed patients were more likely to be females, had fewer years of education, and were more likely to be unemployed. Regarding the epilepsyrelated characteristics, the depressed patients had a longer history of epilepsy, were experiencing seizures more frequently, were receiving more AEDs, and were more likely to receive AEDs with negative psychotropic effects. There were no other statistically significant differences
107
Table 1 Antiepileptic agents used in our study group, and their correspondent psychotropic effects [34,35] regarding depression. Antiepileptic drug
Number
Percentage
Psychotropic effects [34,35]
Levetiracetam Sodium valproate Carbamazepine Oxcarbazepine Topiramate Benzodiazepines Lacosamide Lamotrigine Pregabalin Phenytoin Primidone Phenobarbital Zonisamide
28 27 23 23 22 15 12 9 8 7 6 6 4
29.8% 28.7% 24.5% 24.5% 23.4% 16.0% 12.8% 9.6% 8.5% 7.4% 6.4% 6.4% 4.3%
Negative Neutral Neutral Neutral Negative Negative Limited experience Positive Negative Neutral Negative Negative Negative
regarding the clinical and demographic characteristics between the two groups. The following independent variables were entered into the multivariate logistic regression model: age, sex, education years, employment status (being unemployed or not), duration of epilepsy, seizure frequency, number of AEDs, and type of AEDs (negative psychotropic effect or not). The results of the multivariate logistic regression are shown in Table 3. Adjusted odds ratios are presented. The full model significantly predicted a major depressive episode (χ2 = 37.95, df = 8, p b 0.001) with the majority of the variance (34 to 52%) being explained by three variables: gender, employment status, and seizure frequency. Being a female was associated with a 19.68-fold increase in the odds of having a major depressive episode (95% CI 3.39–114.14, p = 0.001); being unemployed was associated with a 6.46-fold increase in the odds of having a major depressive episode (95% CI 1.23–34.07, p = 0.028), and each extra seizure experienced per month was associated with a 1.38-fold increase in the odds of having a major depressive episode (95% CI 1.03–1.85, p = 0.031). 4. Discussion Our cross-sectional study has estimated that the prevalence of a major depressive episode among the patients with epilepsy treated in the largest Greek hospital in Athens is 22.3%. Moreover, we showed that female gender, unemployment, and increased seizure frequency are factors associated with a major depressive episode. The novelty of our study is that this is the first Greek study that aimed to investigate the prevalence of a major depressive episode and to identify its determinants among patients with epilepsy. Apart from its epidemiological importance for Greece, our study was conducted in an era of a severe financial crisis, which has already led to a dramatic increase of unemployment in the general population. The effects of unemployment on mental health are well described [12]. Depression tends to be more common among the long-term unemployed [13]. In 2011, in the beginning of the crisis, Economou et al. showed that the prevalence of major depression in the general population of Greece had already increased by almost 3 times, jumping from 3.3% to 8.2% [14]. This has also led to a substantial increase in the prevalence of suicidal ideation and reported suicide attempts [15]. Patients with epilepsy may have difficulty in finding and maintaining regular employment. They face appropriate restrictions, such as those relating to driving or working in situations in which they might be liable to injury. They may also be the victims of ignorance and stigma [16]. Additionally, a clear relationship between current seizure frequency and employment status has been demonstrated [17]. However, in our study, we showed that unemployment is independently associated with a major depressive episode after having adjusted for seizure frequency. Seizure frequency has been associated with psychological disturbances in a number of studies. Dias et al. concluded that major
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Table 2 Demographic and clinical characteristics of study total population and subgroups.
Demographic characteristics Female sex (%) Age, in years (SD) Marital status (%) Single Married Divorced Widowed Education years (SD) Employment status (%) Homemaker Full-time student Employed part-time Employed full-time Retired Unemployed Epilepsy-related characteristics Duration of epilepsy, in years (SD) Number of seizures per month (SD) Seizure type (%) Simple partial Complex partial Partial evolving to secondary general Absence Myoclonic Tonic–clonic Atonic Number of AEDs (SD) Receiving AEDs with negative psychotropic effects (%)
Total (n = 94)
Depressed (n = 21)
Nondepressed (n = 73)
p
45 (47.9) 36.8 (13.2)
16 (76.2) 34.7 (11.9)
29 (39.7) 37.3 (13.6)
0.003** 0.425
57 (60.6) 31 (33.0) 5 (5.3) 1 (1.1) 12.7 (3.3)
13 (61.8) 6 (28.6) 1 (4.8) 1 (4.8) 11.2 (2.8)
44 (60.3) 25 (34.2) 4 (5.5) 0 (0.0) 13.0 (3.4)
11 (11.7) 15 (16.0) 8 (8.5) 32 (34.0) 11 (11.7) 17 (18.1)
5 (23.8) 3 (14.3) 2 (9.5) 2 (9.5) 2 (9.5) 7 (33.4)
6 (8.2) 12 (16.4) 6 (8.2) 30 (41.1) 9 (12.4) 10 (13.7)
16.6 (13.1) 1.8 (2.9)
21.7 (11.6) 3.6 (4.3)
15.2 (13.2) 1.3 (2.2)
12 (12.8) 49 (52.1) 18 (19.1) 3 (3.2) 1 (1.1) 10 (10.6) 1 (1.1) 2.0 (1.1) 55 (58.5)
0 (0.0) 14 (66.6) 6 (28.6) 0 (0.0) 0 (0.0) 1 (4.8) 0 (0.0) 2.6 (1.1) 38 (52.1)
12 (16.4) 35 (47.9) 12 (16.4) 3 (4.1) 1 (1.4) 9 (12.4) 1 (1.4) 1.8 (1.0) 17 (81.0)
0.301
0.040*
0.037*
0.048* 0.002**
0.230
0.004** 0.018*
* p b 0.05, ** p b 0.01
depression is associated with uncontrolled seizures, with prevalence double that of patients whose seizures are controlled [18]. In a community-based survey, Jacoby et al. [17] observed that 21% of patients with recurrent seizures were depressed versus 9% of patients with controlled seizures, and O'Donoghue et al. [19] have similarly demonstrated at primary care settings that 33% of patients with recurrent seizures versus 6% of those in remission had probable depression. Overall, the prevalence of depression has been reported to range from 20 to 55% in populations with seizures that are resistant to treatment versus 3–9% in subjects with well-controlled seizures [20]. In an interesting study, aiming to test a theoretical explanatory model of the relationship between depression symptom scores and seizure frequency in people with epilepsy, Thapar et al. concluded that the relationship between depression symptom scores and seizure frequency in those with epilepsy is bidirectional [21]. Our study estimated that each extra reported seizure per month is associated with a 38% increase in the odds of experiencing a major depressive episode. In other words, better seizure control protects patients with epilepsy from depression. However, the occurrence of depression, particularly in patients with high seizure frequency, might seem paradoxical as one of the most powerful treatments for depression is electroconvulsive therapy, which is entirely based on the tenet of the antidepressive effects of convulsions [7].
The effect of gender on the development of psychiatric disturbances in epilepsy has been highly controversial in previous studies, most likely due to diverse methodological approaches and differences in the investigated populations [7,22–27]. Our study has shown that female gender increases the odds of having a major depressive episode. This is consistent with the fact that in the general population, women are more likely than men to suffer from depression; therefore, female gender could be considered a major risk factor for developing this condition also among patients with epilepsy [28]. Moreover, there is a growing body of research that suggests that men are less likely than women to seek help from health professionals [29], which has also been shown in the Greek population [30]. Therefore, the percentage of male patients with epilepsy suffering from a major depressive episode might have been underestimated, especially since there is a higher chance of men having missed their appointments if depressed. Our results should be interpreted with some caution given the limitations of our design. Firstly, although the determinants of depression in our study population are in agreement with those in other studies, the effect of female gender was related to an exceedingly high increase in the odds of having a major depressive episode, a finding that is not supported by other studies. Apart from the fact that this may be explained by the idiosyncrasy of Greek men and their tendency not to seek help
Table 3 Patient characteristics investigated for their association with a major depressive episode. Variable
ORa (95% CI)
Wald
p-Value
Age (per year) Female sex Education (per year) Being unemployed Duration of epilepsy (per year) Monthly frequency (per seizure) Number of AEDs (per extra agent) Receiving AEDs with potentially negative psychotropic effects
0.966 (0.907–1.038) 19.683 (3.394–114.138) 0.882 (0.711–1.094) 6.460 (1.225–34.069) 1.066 (0.992–1.145) 1.381 (1.029–1.853) 0.944 (0.426–2.095) 3.445 (0.675–17.590)
0.894 11.041 1.311 4.837 3.037 4.631 0.020 2.210
0.344 0.001 0.252 0.028 0.081 0.031 0.888 0.137
a
Adjusted odd ratios (OR) presented.
P. Zis et al. / Epilepsy & Behavior 33 (2014) 106–109
when needed, the corresponding confidence intervals of the adjusted odds ratios were ranging widely. This possibly could be explained by our relatively small sample size. Secondly, although we were recording all severely disabling or life-threatening medical comorbidities, such as cancer and stroke, we did not include in our analysis less severe medical comorbidities. Adjusting for such comorbidities is of particular interest, but it also requires a much greater sample size. Despite the fact that our study population included patients of all age groups, education levels, and different types of epilepsy, we had few patients with myoclonic, atonic, and absence seizures. This might have been the reason for not finding statistically significant correlations between seizure type and depression. Moreover, although the diagnosis of epilepsy was based on the ILAE criteria and on documented EEG reports, we could not include in our analysis specific electroclinical findings but only clinically documented seizure type. Finally, our cohort comprised users of one clinical service, and results may not be generalizable to other settings. Diagnosing depression requires psychiatric evaluation; however, useful clinician-rated questionnaires, such as the MINI [10], self-rated generic questionnaires, such as Hamilton Anxiety and Depression Scale [31], or self-rated disease-specific questionnaires, such as the Neurological Disorders Depression Inventory for Epilepsy [32,33], can be used to identify patients experiencing a major depressive episode and, consequently, treat them appropriately. In our study, we used only clinician-rated measures. However, self-completed instruments might offer a useful complement to capture the patient's own report, even in primary care settings. Living in an era of a severe financial crisis, which affects many countries worldwide, clinicians, not only epilepsy specialists, should be aware of the fact that depression is common in patients with epilepsy. Unemployment rates are expected to grow within the next years; therefore, our finding that unemployment is independently associated with depression among patients with epilepsy is especially important. Acknowledgments We are sincerely thankful to the patients who participated in the study. Conflict of interest None. References [1] Seidenberg M, Pulsipher DT, Hermann B. Association of epilepsy and comorbid conditions. Future Neurol 2009;4(5):663–8. [2] Barry JJ, Huynh N, Lembke A. Depression in individuals with epilepsy. Curr Treat Options Neurol 2000;2(6):571–85. [3] LaFrance Jr WC, Kanner AM, Hermann B. Psychiatric comorbidities in epilepsy. Int Rev Neurobiol 2008;83:347–83. [4] Hermann BP, Seidenberg M, Bell B. Psychiatric comorbidity in chronic epilepsy: identification, consequences, and treatment of major depression. Epilepsia 2000;41(Suppl. 2):S31–41. [5] Harden CL. The co-morbidity of depression and epilepsy: epidemiology, etiology, and treatment. Neurology 2002;59(6 Suppl. 4):S48–55. [6] Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004;110(4):207–20. [7] Kimiskidis VK, Triantafyllou NI, Kararizou E, Gatzonis SS, Fountoulakis KN, Siatouni A, et al. Depression and anxiety in epilepsy: the association with demographic and seizure-related variables. Ann Gen Psychiatry 2007;6:28.
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