|Ahead of print publication
Psychiatric comorbidity and quality of life in patients with epilepsy on anti-epileptic monotherapy and polytherapy
Jagriti Yadav1, Priti Singh1, Surekha Dabla2, Rajiv Gupta1
1 Department of Psychiatry, Institute of Mental Health, Pt. B. D. Sharma University of Health Sciences, Rohtak, Haryana, India
2 Department of Neurology, Pt. B. D. Sharma University of Health Sciences, Rohtak, Haryana, India
|Date of Submission||07-Feb-2021|
|Date of Decision||23-Mar-2021|
|Date of Acceptance||18-May-2021|
|Date of Web Publication||23-Jul-2021|
Department of Psychiatry, Institute of Mental Health, Pt. B. D. Sharma University of Health Sciences, H. No-1195/24 Jagdish Colony, Rohtak-124001, Haryana
Source of Support: None, Conflict of Interest: None
Objective: The bio-psycho-social factors affecting the quality of life in patients with epilepsy can be numerous but are often overlooked. The behavioral side effects of anti-seizure medications can be one such potential factor. The aim of the study is to address the effect of the number of anti-seizure medications on the development of psychiatric comorbidity and quality of life in patients with adequate seizure control. Materials and Methods: The study recruited 100 participants with generalized tonic-clonic seizures from a tertiary care center in North India, who were seizure-free from the last 1 month. The study participants were divided into two groups based on whether they were on monotherapy or polytherapy. The two groups were matched for their socio-demographic and clinical profile. We assessed for psychiatric comorbidity in each group using Mini International Neuropsychiatric Interview. All the study participants were given Hindi translated version of quality of life in the epilepsy-31 questionnaire for objective assessment of the quality of life. Results: The patients receiving anti-epileptic polytherapy had significantly higher prevalence of psychiatric comorbidity than patients on monotherapy. Furthermore, the patients on polytherapy scored significantly less on the cognitive domain of quality of life as well as the overall quality of life domain in the epilepsy-31 questionnaire. Conclusion: The patients with epilepsy must be evaluated for psychiatric comorbidity and side effect profile of anti-seizure medications to improve the quality of life. This is particularly more important for patients who are on anti-epileptic polytherapy even if the seizure control is adequate.
Keywords: Epilepsy, Psychiatric comorbidity, Quality of life
|How to cite this URL:|
Yadav J, Singh P, Dabla S, Gupta R. Psychiatric comorbidity and quality of life in patients with epilepsy on anti-epileptic monotherapy and polytherapy. Tzu Chi Med J [Epub ahead of print] [cited 2021 Oct 22]. Available from: https://www.tcmjmed.com/preprintarticle.asp?id=322193
| Introduction|| |
Epilepsy is a chronic neurological condition characterized by recurrent unprovoked seizures. The estimated median lifetime prevalence of epilepsy in developed nations is 5.8/1000. In developing nations the prevalence of epilepsy is 15.4/1000 for rural and 10.3/1000 for the urban population . Globally, epilepsy is among top five neurological disorders in terms of age-standardized disability adjusted life years (DALYs). DALYs from epilepsy were highest in people aged 5 to 29 years as per the Global Burden of Disease Study, 2016 . Furthermore, in developing countries like India, there is a lack of awareness about the nature of the illness, the presence of stigma, and huge treatment gap which further adds to the burden of epilepsy in these nations ,,. Apart from the neurological dysfunction, patients with epilepsy have various comorbid psychological and psychosocial issues that predispose them to various psychiatric disorders ,,. It has been well established that the prevalence of psychiatric disorders is higher among patients with epilepsy than among the general population . Furthermore, it has been observed that addressing psychiatric comorbidity improved the quality of life in patients with epilepsy who had adequate seizure control .
The concept of “Quality of life”  thus provides a new dimension where the patient's point of view is assessed regarding the impact of disease and medical treatment. In this regard, comorbid psychiatric disorders significantly impair the quality of life in patients with epilepsy ,. However, inadequate seizure control has been the single most important therapeutic target and various other factors predisposing to the psychiatric disorders are often underlooked in patients with epilepsy . In our literature review we could find few studies done in the West , to assess factors responsible for the quality of life in patients with epilepsy apart from seizure control. However, there is the paucity of such studies in the Indian context.
It has been well known that anti-seizure medications have both positive as well as negative psychotropic effects ,,. It has been argued that cognitive side effects of anti-seizure medications, namely, psychomotor slowing , are frequently missed by clinicians. Thus the effects of anti-seizure medications can be considered as potentially important predictors of quality of life in patients with epilepsy. The present study is therefore aimed to address the contribution of anti-epileptic monotherapy and polytherapy to psychiatric comorbidity and quality of life in patients with epilepsy who were seizure-free for a certain period.
| Materials and Methods|| |
Study setting and design
The study was a cross-sectional study conducted in the outpatient department of Psychiatry and Neurology at Pt. B. D. Sharma PGIMS, Rohtak. The study received ethical clearance from the Institutional Ethics Committee (vide letter no. IEC/04). A written informed consent was obtained from each of the study participants. One hundred patients with generalized tonic-clonic seizures meeting the study criteria were recruited over a period of 1 year, ranging from January 2019 to December 2019. The participants were asked to fill the Self-administered Quality of Life in Epilepsy-31 questionnaire (QOLIE-31) .
Out of the one hundred participants, 50 patients who were on anti-epileptic “Monotherapy” constituted Group 1 and the rest 50 who were on “Polytherapy” constituted Group 2. To keep the two groups homogenous, patients with more than 18 years of age, having generalized tonic-clonic seizures and on stable doses of anti-seizure medications were included in the study.
The patients in the two groups were comparable in terms of seizure control and had been on regular follow up since the last 1 year. The presence of any other chronic medical illness, mental and behavioral disorders due to substance, intellectual disability, and speech or hearing disability constituted the exclusion criteria for the study.
The diagnosis of epilepsy was confirmed by the author S. D. following which detailed socio-demographic and clinical variables of the study participants were recorded in a self-designed form. Sociodemographic data included: age, sex, marital status, education level, and socioeconomic status. The clinical variables included: age of onset of epilepsy, total duration of epilepsy, duration from last seizure episode, anti-epileptic treatment, and history of comorbid medical, psychiatric, or substance use disorders.
Mini International Neuropsychiatric Interview Version 6.0.0
The psychiatric comorbidity was assessed using the Mini International Neuropsychiatric Interview Version 6.0.0 . It is a brief structured interview for screening and diagnosis of Major Axis 1 psychiatric disorders in DSM IV and ICD 10. This tool is developed jointly by clinicians and psychiatrists from United States and Europe. It can be administered by the clinicians in a small period which is approximately 15 min. Furthermore, MINI 6.0.0 overcomes the impediment of the two-stage interview process.
There are screening and diagnostic modules for 17 most common psychiatric diagnostic categories. The patient's verbal responses are recorded with the phrases “yes” or “no” in each module by the clinician. “Suicidality” is one of the modules which assesses the intent of harming oneself, active or passive death wishes and any plans for self-harm.
Quality of Life in Epilepsy-31 Version 1.0
The quality of life was assessed using the Self-administered QOLIE-31 Scale. QOLIE-31 is a validated instrument containing seven multi-item scales which include seizure worry, overall quality of life, emotional well-being, energy, cognitive, medication effects, and social function. It is a shorter version of the QOLIE-89 inventory and its Hindi translated version was used for the ease of study participants. QOLIE-31 questionnaire has been validated in Hindi ,. The overall score range was 0–100. The higher the score the better will be the quality of life. Cronbach's alpha and intraclass correlation coefficients obtained for QOLIE-31 in the present study were 0.946 and 0.974, respectively, which indicated good internal consistency and reproducibility of the tool for assessment of QoL for the subjects of the present study.
Descriptive statistics including mean and standard deviation were calculated for continuous variables. Since the main goal of this study was to compare the effects of anti-epileptic mono-therapy and poly-therapy with regard to the prevalence of psychiatric comorbidity and quality of life in patients with epilepsy, Chi-square test on discrete data for psychiatric comorbidity, independent sample t-test, and analysis of variance for all domains of QOLIE-31 scale were performed. The P value specified for significance was < 0.05.
| Results|| |
One hundred patients with generalized tonic-clonic seizures enrolled for the study were divided into two groups based on the prescribed number of anti-seizure medications. The patients on single anti-seizure medication constituted Group I (Mono-therapy group) and the patients on two or more anti-seizure medications constituted Group II (Poly-therapy group).
Socio-demographic and clinical characteristics of the study groups
The socio-demographic and clinical profiles of the study groups are summarized in [Table 1]. The mean age of the study population was around 27.88 ± 8.51 years. The mean Body Mass Index among males was 25.24 ± 3.42 and among females 24.06 ± 4.42. The Mean age of onset of seizures in the study population was 20.73 ± 9.71 years. The mean total duration of epilepsy was 7.12 ± 4.98. The socioeconomic status was assessed using the Modified Kuppuswamy Socioeconomic grading scales with the income range of the year 2012 . There was no significant difference in the sociodemographic profile of the two groups (P > 0.05).
|Table 1: Comparison of Group I and Group II on sociodemographic variables using Chi-square test|
Click here to view
Comparative analysis of scores on domains of Quality of Life in Epilepsy-31 scale between “age of onset of epilepsy” of the study population
One-way ANOVA or analysis of variance test was done to assess the difference of scores of various domains of QOLIE-31 scale, if any, among different age of onset categories of epilepsy of the study population. In none of the variables, the assumptions of the test were violated.
There was no statistically significant difference in any domain score among different age of onset categories as suggested by P value > 0.05 [Table 2].
|Table 2: Comparative analysis of scores on domains of quality of life in epilepsy - 31 Scale between “age of onset of epilepsy” of the study population using one-way ANOVA|
Click here to view
Comparative analysis of scores on domains of Quality of Life in Epilepsy-31 scale between “Total duration of epilepsy” subgroups of the study population
One-way ANOVA or analysis of variance test was done to assess the difference of scores of various domains of QOLIE-31 scale, if any, among different “total duration of illness” subgroups of the study population. In none of the variables, the assumptions of the test were violated. Score on all the domains varied due to the total duration of epilepsy.
There was a significant main effect of the total duration of illness on the domains of energy/fatigue and cognitive functions [Table 3].
|Table 3: Comparative analysis of scores on domains of quality of life in epilepsy - 31 Scale between “total duration of epilepsy” subgroups of the study population using one-way ANOVA|
Click here to view
Psychiatric comorbidity among study groups
Out of 50 patients on Mono-therapy, 5 patients had major depressive disorder, 4 had anxiety spectrum disorders and 2 had suicidality. Out of 50 patients on Poly-therapy, 16 patients had major depressive disorder, 14 had anxiety spectrum disorders and 9 had suicidality. The use of Poly-therapy was significantly associated with psychiatric comorbidity with P < 0.05 [Table 4.]
|Table 4: Comparative analysis of psychiatric comorbidity among study groups using Chi-square test|
Click here to view
Psychiatric comorbidity and individual ASMs in the mono-therapy group
Out of 50 patients on Mono-therapy, there were 16 patients on Valproate out of which 7 had psychiatric comorbidity. Out of 14 patients on Phenytoin, 8 had psychiatric comorbidity and out of 20 patients on Levetiracetam, 8 had psychiatric comorbidity. However, there was no significant difference between the three anti-seizure medications (P > 0.05) [Table 5].
|Table 5: Comparative analysis of psychiatric comorbidity and individual anti-seizure medication in the monotherapy group|
Click here to view
Quality of life in study groups
Score on all the domains on the QOLIE-31 scale varied due to differences in treatment type. The mean overall quality of life score in patients on anti-epileptic monotherapy was 59.78 ± 18.14. The mean overall quality of life score in patients on anti-epileptic polytherapy was 37.58 ± 18.45. The difference in overall quality of life was statistically significant (P value < 0.05). The difference in the two treatment type was also statistically significant on the domain of cognitive functions with P < 0.05 [Table 6].
|Table 6: Comparative analysis of scores on domains of quality of life in epilepsy - 31 Scale with treatment therapy using independent t-test|
Click here to view
| Discussion|| |
The study is one of a kind from a developing nation to assess the independent association of the number of anti-seizure medications with psychiatric comorbidity and quality of life in patients with epilepsy. The sociodemographic and clinical confounders were kept to the minimum in our study. In our study, we found a significant effect of the total duration of epilepsy on the domains of energy/fatigue and cognitive functions on the QOLIE-31 scale. The findings of Auriel et al.  are not consistent with our study findings.
Although there was a trend of decreasing scores of QoL in those with longer duration in the study by Auriel et al., it was not significant. The prevalence of psychiatric comorbidity was 38% in patients on monotherapy as against 66% among those on polytherapy. These findings are consistent with the findings of the study conducted by Vujisis263; et al.  in which prevalence of depression was 72.72% in patients on three or more anti-seizure medications as compared to only 15.38% among patients on monotherapy. The prevalence of depression, anxiety, and suicidality was significantly higher in patients on polytherapy (P < 0.05). The mechanism of anti-seizure medications could be associated with higher risk of depressive symptoms among those on polytherapy ,.
This significant difference in prevalence reinforces the findings from the previous studies ,. In 2008 United States Food and Drug Administration had also alerted regarding the potential risk of suicidality due to anti-seizure medications . The caution for suicidality appears to be more with newer anti-seizure medications as proposed by Andersonhn et al. in their study. There was more risk of depressive symptoms and self-harm with Levetiracetam than for the conventional anti-seizure medications, phenytoin, valproate, and carbamazepine . However, in our study, there was no significant difference within the monotherapy group among different anti-seizure medications.
Our results further align with findings of another study by Auriel et al.  which supported side effects of anti-epileptic drugs monotherapy as an important factor responsible for the poor quality of life even in well-controlled epilepsy. The cognitive domain on the QOLIE-31 scale was significantly affected in patients on polytherapy (P = 0.015) in our study. The adverse effects of anti-seizure medications, cognitive deficits, in particular, are not surprising and the negative impact on quality of life is well established in the literature ,,. The common pathological mechanism  underlying epilepsy and depressive disorder further add to the cognitive decline in patients with epilepsy secondary to the affective state.
Therefore, it becomes empirical for the clinicians to give due consideration to various potential factors responsible for psychiatric comorbidity in epilepsy patients, in particular the effects of anti-seizure medications. It will promote adherence, seizure control, emotional well-being, and socio-occupational functioning. Our study thus addresses the direct role of the clinician with respect to the rational use of anti-seizure medications, detailed inquiry about the side-effects of anti-seizure medications along with symptoms of psychiatric disorders. Certain tools like the SIDAED questionnaire can be used to assess the patient-reported adverse effects of anti-seizure medications and their impact on the patient's outcome . This will provide more accurate information of patients' concerns which, if timely addressed, can provide a better quality of life in patients with epilepsy.
Limitation of the study
The study was limited by the cross-sectional design. The other limitation is that the QOLIE-31 questionnaire does not provide an elaborative side effect profile of anti-seizure medications. Thus, the study does not take into account the detailed side effect profile of individual pharmacological agents. Moreover, the patients on anti-epileptic polytherapy may also have more negative experiences in terms of long duration of uncontrolled epilepsy and more severe disease that may be considered as confounding factors contributing to more psychiatric comorbidity in the polytherapy group.
| Conclusion|| |
The burden of epilepsy as well as treatment gap for epilepsy and psychiatric disorders is huge in developing nations. Anti-seizure medications are prescribed on long-term basis and hence have a higher potential to cause adverse drug reactions. Furthermore, they are known to cause cognitive and other behavioral deficits. The psychiatric disorders in patients with epilepsy are often missed and therapeutic opportunities are lost which can significantly impair the quality of life in them. Therefore, systematic identification of neuropsychiatric complications of anti-seizure medications must be done by the clinicians even in patients with adequately controlled seizures.
More pragmatic quality of life assessment tools can be developed for use in outpatient clinics; to monitor the treatment outcomes including the neuropsychiatric adverse effect profile of anti-seizure medications.
The authors acknowledge the patients' cooperation and consent to participate in the study. We would like to express our deepest gratitude to QOLIE Development Group for granting permission for using the translated version of the scale and for their immense cooperation during the entire process.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Estimation of the burden of active and life-time epilepsy: A meta-analytic approach. Epilepsia 2010;51:883-90.
GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:459-80.
Nizamie SH, Akthar S, Banerjee I, Goyal N. Health care delivery model in epilepsy to reduce treatment gap: World Health Organization study from a rural tribal population of India. Epilepsy Res 2009;84:146-52.
Kale R. Global Campaign Against Epilepsy: The treatment gap. Epilepsia 2002;43(Suppl 6):31-3.
Meyer AC, Dua T, Ma J, Saxena S, Birbeck G. Global disparities in the epilepsy treatment gap: A systematic review. Bull World Health Organ 2010;88:260-6.
Osman A, Seri S, Cavanna AE. Clinical characteristics of patients with epilepsy in a specialist neuropsychiatry service. Epilepsy Behav 2016;58:44-7.
Hessen E, Lossius MI, Gjerstad L. Behavioural adjustment in seizure-free epilepsy patients on monotherapy. Seizure 2008;17:422-30.
Munger Clary HM, Snively BM, Hamberger MJ. Anxiety is common and independently associated with clinical features of epilepsy. Epilepsy Behav 2018;85:64-71.
Ettinger A, Reed M, Cramer J; Epilepsy Impact Project Group. Depression and comorbidity in community-based patients with epilepsy or asthma. Neurology 2004;63:1008-14.
Puka K, Smith ML. Predictors of long-term quality of life after pediatric epilepsy surgery. Epilepsia 2015;56:873-81.
World Health Organisation Quality of Life Group. What quality of life? The WHOQOL Group. World Health Organization quality of life assessment. World Health Forum 1996;17:354-6.
Melikyan E, Guekht A, Milchakova L, Lebedeva A, Bondareva I, Gusev E. Health-related quality of life in Russian adults with epilepsy: The effect of socio-demographic and clinical factors. Epilepsy Behav 2012;25:670-5.
Azuma H, Akechi T. Effects of psychosocial functioning, depression, seizure frequency, and employment on quality of life in patients with epilepsy. Epilepsy Behav 2014;41:18-20.
Auriel E, Landov H, Blatt I, Theitler J, Gandelman-Marton R, Chistik V, et al. Quality of life in seizure-free patients with epilepsy on monotherapy. Epilepsy Behav 2009;14:130-3.
Pirio Richardson S, Farias ST, Lima AR 3rd
, Alsaadi TM. Improvement in seizure control and quality of life in medically refractory epilepsy patients converted from polypharmacy to monotherapy. Epilepsy Behav 2004;5:343-7.
Mula M, Agrawal N, Mustafa Z, Mohanalingham K, Cock HR, Lozsadi DA, et al. Self-reported aggressiveness during treatment with levetiracetam correlates with depression. Epilepsy Behav 2015;45:64-7.
Harden CL, Goldstein MA. Mood disorders in patients with epilepsy: Epidemiology and management. CNS Drugs 2002;16:291-302.
Schmitz B. Effects of antiepileptic drugs on mood and behavior. Epilepsia 2006;47(Suppl 2):28-33.
Gupta M, Patelm P, Gandhi A, Desai M. Effect of antiepileptic drugs on psychomotor functions and memory in epilepsy patients. J Young Pharm 2017;9:357-61.
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. Epilepsia 1998;39:81-8.
Sheehan D, Janavs J, Harnett-Sheehan K, Sheehan M, Gray C, Lecrubier Y, et al. Mini international neuropsychiatric interview. Ver. 6.0. Tampa, USA: University of South Florida College of Medicine, Paris, France: Centre Hospitalier Sainte-Anne; 2009.
Mehta S, Tyagi A, Tripathi R, Kumar M. Study of inter-relationship of depression, seizure frequency and quality of life of people with epilepsy in India. Ment Illn 2014;6:5169.
Mehndiratta MM, Alam A, Pandey S, Singh E. Assessment of quality of life in Indian adults with epilepsy and their caregivers. Int J Epilepsy 2015;2:11-8.
Bairwa M, Rajput M, Sachdeva S. Modified kuppuswamy's socioeconomic scale: Social researcher should include updated income criteria, 2012. Indian J Community Med 2013;38:185-6.
] [Full text]
Vujisić S, Vodopić S, Radulović L, Injac-Stevović L. Psychiatric comorbidities among patients with epilepsy in Montenegro. Acta Clin Croat 2014;53:411-6.
Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf 2007;30:555-67.
Brent DA, Crumrine PK, Varma RR, Allan M, Allman C. Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics 1987;80:909-17.
Kanner AM, Barry JJ, Gilliam F, Hermann B, Meador KJ. Depressive and anxiety disor- ders in epilepsy: Do they differ in their potential to worsen common antiepileptic drug-related adverse events? Epilepsia 2012;53:1104-8.
Au A, Leung P, Kwok A, Li P, Lui C, Chan J. Subjective memory and mood of Hong Kong Chinese adults with epilepsy. Epilepsy Behav 2006;9:68-72.
U.S.Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Translational Sciences, Office of Biostatistics. Statistical Review and Evaluation: Antiepileptic Drugs and Suicidality; 2008.
Andersonhn F, Schade R, Willich SN, Garbe E. Use of antiepileptic drugs in epilepsy and the risk of self harm or suicidal behaviour. Neurology 2010;75:335-40.
Lam CL, Lauder IJ. The impact of chronic diseases on the health-related quality of life (HRQOL) of Chinese patients in primary care. Fam Pract 2000;17:159-66.
Sprangers MA, de Regt EB, Andries F, van Agt HM, Bijl RV, de Boer JB, et al. Which chronic conditions are associated with better or poorer quality of life? J Clin Epidemiol 2000;53:895-907.
Hesdorffer DC, Ishihara L, Webb DJ, Mynepalli L, Galwey NW, Hauser WA. Occurrence and reccurence of attempted suicide among people with epilepsy. JAMA Psychiatry 2016;73:80-6.
Weintraub D, Buchsbaum R, Resor SR Jr., Hirsch LJ. Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy. Epilepsy Behav 2007;10:105-10.
Uijl SG, Uiterwaal CS, Aldenkamp AP, Carpay JA, Doelman JC, Keizer K, et al.
A cross-sectional study of subjective complaints in patients with epilepsy who seem to be well-controlled with anti-epileptic drugs. Seizure 2006;15:242-8.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]