Epilepsy & Behavior 29 (2013) 77–81
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Pharmacological treatment of psychiatric comorbidity in patients with refractory epilepsy Mohamad Karouni a, Oliver Henning b, Pål G. Larsson c, Svein I. Johannessen b,d, Cecilie Johannessen Landmark e,⁎ a
Jæren Apotek Varhaug, Norway The National Center for Epilepsy, Sandvika, Oslo University Hospital, Oslo, Norway Dept. of Neurosurgery, Oslo University Hospital, Oslo, Norway d Dept. of Pharmacology, Oslo University Hospital, Oslo, Norway e Dept. of Pharmacy and Biomedical Science, Faculty of Health Science, Oslo and Akershus University College, Oslo, Norway b c
a r t i c l e
i n f o
Article history: Received 8 February 2013 Revised 6 June 2013 Accepted 29 June 2013 Available online 9 August 2013 Keywords: Antiepileptic drugs Epilepsy Psychiatric comorbidity Psychotropic drugs
a b s t r a c t The purpose of the present study was to describe the use of psychopharmacological drugs for the treatment of a stated or presumed psychiatric comorbid condition in patients with refractory epilepsy and discuss the clinical implications of such treatment. The study was a retrospective descriptive study in patients admitted to the National Center for Epilepsy in Norway based on medication described in medical records. The mean age was 40 years (range: 9–90), and the gender ratio was 56/44% female/male. Psychotropic drugs (antidepressants and antipsychotics) were used to a lower extent than in the general population in Norway. Drugs for ADHD were predominantly used in children. The prevalence of patients treated with psychiatric comedication was 13% (143 of 1139 patients). The patients used two to eight concomitant CNS-active drugs, which calls for the close monitoring of potential pharmacodynamic and pharmacokinetic interactions and should challenge clinicians to achieve a less complex pharmacotherapy. Psychiatric comorbidity is an important concern in patients with refractory epilepsy and may be undertreated. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Approximately 1% of the population worldwide suffers from epilepsy, and antiepileptic drugs (AEDs) are often used for life-long treatment, which increases the susceptibility of interactions with concomitant medication. The incidence of psychiatric disorders in patients with epilepsy is significantly higher than in the general population and may have serious implications for the patients [1]. A range of prevalence rates of depression, anxiety, schizophrenia, or bipolar disorder in epilepsy between 6% and greater than 30% has been demonstrated with various methods [2–5]. Depression can have a greater impact on the quality of life of patients with epilepsy than seizure frequency and results in a poorer prognosis [6,7]. This finding highlights the importance of the documentation and treatment of psychiatric comorbidity in epilepsy. The total drug load in these patients is often significant and includes up to eight CNS-active drugs used concomitantly [5]. Patients with refractory epilepsy are a vulnerable group because they suffer from a chronic disease with little apparent hope for a cure. These patients live with unsatisfactory seizure control and often use
⁎ Corresponding author at: Dept. of Pharmacy and Biomedical Science, Faculty of Health Science, Oslo and Akershus University College, Pilestredet 50, N-0167 Oslo, Norway. Fax: +47 22 45 23 35. E-mail address:
[email protected] (C. Johannessen Landmark). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.06.031
polytherapy with a narrow balance between efficacy and tolerability [1,5]. Recent studies have demonstrated that 40–49% of patients with refractory focal epilepsy suffer from psychiatric comorbidities [8,9]. The purposes of the present study were to describe the use of psychopharmacological drugs for the treatment of a stated or presumed psychiatric comorbid condition in patients with refractory epilepsy and to discuss the clinical implications of such treatment. 2. Methods 2.1. Study material The present investigation was a descriptive, retrospective study in which psychiatric comedication in patients with refractory epilepsy admitted to the National Center for Epilepsy, Sandvika, Oslo University Hospital from 01.07.2007 to 31.12.2008 was registered. The center is also a referral center for children with epilepsy and behavioral symptoms. Inclusion criteria included an epilepsy diagnosis, use of at least one AED for epilepsy and at least one of the following Anatomical Therapeutic Chemical classification system (ATC) classes of AEDs (N03A) and drugs used in psychiatry: N05A-antipsychotics (including lithium), N05B-anxiolytics, N06A-antidepressants, N06B-centrally acting sympathomimetics, or N03A-antiepileptic drugs used in a psychiatric indication [10]. Exclusion criteria were patients who did not fulfill the
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inclusion criteria or if they used drugs in the ATC class N05BAbenzodiazepines acutely only in cases of seizures as an anticonvulsant (diazepam or midazolam), as stated in the medical record as the only potential psychotropic drug. Thus, the patients who used benzodiazepines were included as users of psychotropic drugs only if they were prescribed for a clearly stated psychiatric indication, such as anxiety. Psychiatric disorders described in the medical records were sorted according to the International Statistical Classification of Diseases and Related Health Problems (ICD-10) code system, namely, the Mental and Behavioural Disorders (F00–99) [11]. The drugs were used according to a given diagnosis. Special emphasis was put on schizophrenia (F20–29), mood (affective) disorders (F30–39), and behavioral and emotional disorders with onset usually occurring in childhood and adolescence (F90–F98), in which psychotropic drugs most frequently are prescribed. In cases where psychopharmacological treatment was stated but no psychiatric diagnosis given, these patients were placed in a possible psychiatric diagnosis category based on their psychopharmacological treatment; anxiolytics for anxiety, antidepressants for depression, antipsychotics for schizophrenia/bipolar disorder (which could not be distinguished based on the medication and included antipsychotics and lithium), and centrally active stimulants for attention-deficit disorder. 2.2. Data handling and analyses The medical record system Siemens DocuLive EPJ was used. The collected variables included gender, age, seizure types, diagnosis other than epilepsy, and use of AEDs and drugs for psychiatric disorders. All data were handled anonymously by assigning each patient a number. The study was approved by the Regional Ethics Committee in Norway. No statistical tests were performed as the study was a descriptive study. Data regarding the utilization of psychotropic drugs (antidepressants, anxiolytics, centrally acting sympathomimetics, and antipsychotics) in the entire population of Norway were obtained from the National Prescription Registry [12]. According to Statistics Norway, the number of inhabitants in Norway in 2008 was 4,737,171 [13]. 3. Results 3.1. Characteristics of the patient population Characteristics of the patients and seizure classification are shown in Table 1. The average age of the entire patient population was 40 years with a slight predominance of women, and 85% of the patients were adults (121 patients). The majority of patients had one or two seizure types (57 and 53 patients, respectively), but up to five seizure types were stated (1 patient).
3.2. Utilization of antiepileptic drugs in patients with psychiatric comorbidity Lamotrigine, valproic acid, and levetiracetam were the most commonly used AEDs in epilepsy, accounting for 50% of the patients (Fig. 1). Lamotrigine was used in all age groups. Levetiracetam was used in children and adults. Valproic acid was used in children and adults and less in the elderly older than 65 years, while carbamazepine was exclusively used in adults and the elderly. The patients used one to five concomitant AEDs. The AEDs not included in Fig. 1 were used by less than 10 patients (in descending order): nitrazepam, pregabalin, sulthiame, lacosamide, stiripentol, tiagabine, vigabatrin, acetazolamide, eslicarbazepine acetate, ethosuximide, and felbamate. No patients were prescribed AEDs (lamotrigine, valproic acid, or carbamazepine) for a psychiatric indication as a mood stabilizer. 3.3. Utilization of psychotropic drugs Children more frequently used drugs for ADHD, while adults and elderly patients used antidepressants and anxiolytics (Fig. 2). The majority of adults using antidepressants received selective serotonin reuptake inhibitors (SSRI) (55 patients) compared to seven patients who used selective noradrenaline reuptake inhibitors, six patients who used tricyclic antidepressants, and three who used other antidepressants. Regarding observed gender differences, women used escitalopram (21 W/9 M), diazepam (11 W/7 M), oxazepam (5 W/3 M), and quetiapine (5 W/2 M) to a larger extent than men, while men more commonly used olanzapine (1 W/7 M) and haloperidol (1 W/4 M). Twenty-three of the patients using antipsychotics (38 patients) (60%) received the second-generation drugs (olanzapine, risperidone, quetiapine), while 15 patients used first-generation drugs (haloperidol, levomepromazine, and lithium). The patients used one to five concomitant psychotropic drugs, where 24% of them used two or more of these drugs. The use of drugs for psychiatric disorders in the study population was compared to the total population in Norway, as shown in Table 2, and it was found that antidepressants and anxiolytics were used less than in the population as a whole (12% and 29% less, respectively). Antipsychotics were used to a similar extent, while centrally acting sympathomimetics were used five times more in the study population than in the total population of Norway. 3.4. Polytherapy of AEDs and psychotropic drugs The total drug load of the patients was two to eight concomitant CNS-active drugs (AEDs and psychotropic drugs). The majority of the patients used two to four drugs (74%) (n = 174), while 26% (n = 62) used five or more drugs. The mean number of drugs used concomitantly was 1.65 (n = 236 users among the 143 patients with psychiatric
Table 1 Characteristics of the study population. Patient characteristics
Number of patients (women/men) (%)
Mean age, years Age groups Children (9–18) Adults (19–64) Elderly (65–90) Total Seizure classification Generalized tonic–clonic seizures Absence seizures Tonic, myoclonic, atonic seizures Complex partial seizures Simple partial seizures Unspecified seizures Psychogenic non-epileptic seizures (PNES)
40 (range: 9–90) 22 (11 W/11 M) (15%) 108 (59 W/49 M) (76%) 13 (10 W/3 M) (9%) 143 (80 W/63 M) (56/44%) 17 3 3 (1/1/1) 17 2 15 16
Fig. 1. The utilization of antiepileptic drugs (AEDs) in children, adults, and the elderly with psychiatric comorbidity (143 patients used 540 AEDs in total; 179 in children, 201 in adults, and 160 in the elderly). The AEDs used by 10 patients or more are shown in the figure.
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Fig. 2. Utilization of psychoactive drugs categorized in main indications in children, adults and the elderly (143 patients used 191 psychoactive drugs in total; 26 in children, 146 in adults, and 19 in the elderly). Note that the use of methylphenidate among children was as high as 77%.
comorbidity). This trend gives rise to a considerable risk for pharmacokinetic interactions among the drugs in use, and possible clinical implications are summarized in Table 3.
who were treated for both depression and anxiety. Treatment of ADHD occurred in all of the included children (15% of the study population) (Fig. 3b).
3.5. Presumed psychiatric comorbidity based upon psychopharmacological treatment in patients with refractory epilepsy
4. Discussion 4.1. The utilization of antiepileptic drugs
We studied 1139 patient records, and 143 (13%) of the patients used psychopharmacological comedication. Figs. 3a and b show the presumed prevalence of the main categories of psychiatric diagnoses based upon one or more stated diagnoses in 134 out of 143 patients (94%). Depression occurred most frequently and was most common in female adults. Among the remaining nine included patients (6%), utilization of psychotropic medication was stated without a given diagnosis, and a presumed psychiatric comorbid diagnosis was then based on their medication and additional documentation or reports stated in their medical records. These patients were placed in a possible psychiatric category based on their psychopharmacological treatment (see Methods for details). In total, one or more psychiatric diagnoses were reported in 94% of the patients using psychotropic medication (179/134), giving an average number of 1.33 stated psychiatric diagnoses per patient. There were twice as many women than men
Table 2 Comparison of the use of drugs for psychiatric disorders at the referral center compared to the entire population in Norway. Drug class
ATC code
Study population
Prevalence (%)
Norway
Prevalence (%)
Antipsychotics Anxiolytics Antidepressants Centrally acting sympathomimetics
N05A N05B N06A N06B
25 49 61 30
2.19 4.30 5.36 2.63
104,086 285,497 288,414 25,207
2.20 6.02 6.09 0.53
Number of inhabitants in Norway in 2008: 4,737,171 (ssb.no). Number of patients included in the study: 1139. Number of patients using drugs for psychiatric disorders in Norway obtained from the Norwegian Prescription Registry (reseptregisteret.no).
The most commonly used AEDs in epilepsy were lamotrigine, levetiracetam, and valproic acid, which accounted for 45% of the total use. Lamotrigine is also increasingly used in psychiatry, as it has been demonstrated to have antidepressant effects in patients with epilepsy and depressive symptoms and is commonly used in this patient group [14–17]. This enables a rational choice of a proper AED in many patients with epilepsy and psychiatric comorbid disorders. It cannot be excluded that some of the patients with mood disorders have been given lamotrigine (or valproic acid or carbamazepine) as an AED and that a psychiatric diagnosis or the benefit of treatment with lamotrigine has not been stated in their medical records. Levetiracetam may cause neuropsychiatric effects, such as agitation and depression, or worsen psychiatric symptoms [18], and these symptoms might be misinterpreted as a psychiatric comorbid disorder. The choice of the newer AEDs that were used is also in accordance with their use in the rest of the country and in previous studies, including those of patients admitted to our center [17,19,20]. 4.2. The utilization of psychotropic drugs The surprisingly low utilization of antidepressant and anxiolytic drugs points to a possible underdiagnosis and undertreatment of this group of patients with refractory epilepsy and psychiatric comorbidity, as discussed above [21,22]. Antipsychotic drugs were used to a similar extent as the population as a whole, which also points to a possible undertreatment because various studies demonstrate a higher prevalence of psychosis in patients with epilepsy [2,4]. Due to low sample sizes, the observed differences between drug utilization in men and women were not tested statistically. The utilization of antidepressants,
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Table 3 Antiepileptic drugs and psychotropic drugs in use that are involved in pharmacokinetic (PK) interactions. Drug class
Characteristics
Potential for PK interactions
Clinical implications
Antiepileptic drugs (AEDs) Carbamazepine
Enzyme inducer of CYPs and UGTs
High
Valproic acid
Enzyme inhibitor of CYPs and UGTs
High
Lamotrigine
Metabolized through UGT. Affected by inducers and inhibitors
High
Lower serum concentrations of other AEDs (e.g., lamotrigine) and various psychotropic drugs (e.g., fluoxetine, fluvoxamine, nefazodone, olanzapine, risperidone) Higher serum concentrations of other AEDs (e.g., lamotrigine, carbamazepine) or lower concentrations of psychotropic drugs as clozapine Lower or higher serum concentrations of lamotrigine when used in combination with other drugs (e.g., carbamazepine, phenobarbital, phenytoin, oxcarbazepine, valproic acid, chlorpromazine, olanzapine)
Enzyme inhibitor or inducer of CYPs and UGTs Enzyme inhibitors of CYPs and UGTs
High
Psychotropic drugs Risperidone (antipsychotic) Sertraline, fluoxetine (SSRIs)
High
Higher serum concentrations of AEDs as carbamazepine or higher or lower concentrations of valproic acid when used in combination Higher serum concentrations of AEDs (carbamazepine, phenobarbital, phenytoin) or lower concentrations of valproic acid when used in combination
Potential for PK interactions is based upon [25–27], and relevant examples of drugs are included. CYP = cytochrome P 450, phase I enzymes; UGT = uridine glucuronosyltransferase, phase II enzymes.
primarily SSRIs and antipsychotics of the second-generation drugs, is similar to our previous population-based study and is in accord with recent recommendations [5,23]. The National Center for Epilepsy is also a referral center for children with epilepsy and behavioral problems, especially ADD/ADHD. Thus, there is a selection bias that explains the high degree of treatment for ADHD, which is in line with the findings of other studies [17,19,24]. 4.3. Clinical implications of polytherapy of AEDs and psychotropic drugs Efficacy and tolerability may be affected by pharmacokinetic and pharmacodynamic interactions in patients with polytherapy. In the present study, two to eight CNS-active drugs were used in combination,
many of them with significant potential for drug interactions [25,26]. At our center, a common approach to such complex polytherapy and drug load is to start the tapering off of one or more drugs at admission, which often leads to fewer adverse effects and improved cognitive function. One of the most common causes of admission is an evaluation of the medication [17,19]. Regarding the utilization of AEDs, the older drugs, including the enzyme inducers carbamazepine, phenytoin, and phenobarbital and the inhibitor valproic acid, are most likely to cause pharmacokinetic interactions in combination with other AEDs or other drugs, as summarized in Table 3. The newer drugs, such as lamotrigine, levetiracetam, and topiramate, have a low to intermediate potential for interactions. The metabolism of lamotrigine may, however, be affected by both enzyme inducers and inhibitors [25]. Most antidepressants and antipsychotics are metabolized through the hepatic CYP-system and may be affected by AEDs or inhibit (sertraline, fluoxetine) the metabolism of other drugs [26,27]. Precautions and close monitoring of AEDs by the implementation of therapeutic drug monitoring may control for pharmacokinetic variability and interactions [28]. This variability is also important to consider for psychotropic drugs, as it has been demonstrated that female gender and old age are important factors that contribute to pharmacokinetic variability and lower serum concentrations of antidepressants [29]. All CNS-active drugs used in combination may cause unintended pharmacodynamic interactions, resulting in excessive adverse effects, therefore requiring attention when adding another drug. Children concomitantly treated for ADHD and elderly patients treated with anxiolytics or antidepressants may be more vulnerable and sensitive to such interactions. The treatment of epilepsy and comorbid psychiatric disorders requires a rational pharmacological approach regarding the proper choice of drugs, susceptibility to drug interactions, tolerability, and optimal efficacy to avoid seizures. Information and education of patients may improve the treatment outcome, including compliance and psychiatric symptoms. 4.4. Presumed psychiatric comorbidity based upon psychopharmacological treatment in patients with refractory epilepsy
Fig. 3. Presumed prevalence of psychiatric comorbidity in patients with refractory epilepsy with a focus on gender and age. One or more psychiatric diagnosis was given in 134 out of the 143 included patients (94% of the population), while the remaining nine patients were placed in a possible psychiatric category based on their psychopharmacological treatment (see text for details). a) Prevalence of psychiatric disorders divided by gender, men (n = 63) and women (n = 80), 143 patients in total and b) in children (n = 22), adults (n = 108), and the elderly (n = 13).
The study shows that 13% of the patients with refractory epilepsy admitted to a referral center received psychopharmacological treatment in addition to AEDs for epilepsy. Other treatment options such as psychotherapeutic or other somatic forms of psychiatric treatment were not investigated in this study. Psychiatric populations differ in severity and quality of symptoms, thereby requiring different forms of treatment. Based on the documented use of psychiatric medication, the actual psychiatric comorbidity can only be an estimate. The findings are in line with a previous study that included 167 patients with epilepsy, in
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which 13% (n = 22) used psychotropic drugs. Neurologists may be reluctant to state a psychiatric diagnosis during a stay at the referral center where the epilepsy is a main focus. An additional 13% were considered by their clinician to have clinically significant psychiatric symptoms, pointing to an undertreatment of psychiatric comorbid disorders [21]. The literature concerning this subject is sparse and exhibits variable results; however, one may assume that at least 50% of the patients with a psychiatric comorbidity are not receiving pharmacological treatment [21,22]. Therefore, it seems reasonable to assume that the prevalence of psychiatric comorbidity in the present study is at least 26%, which is comparable to larger population-based studies of up to N30% [2–5,8,9,14]. Patients with refractory epilepsy are a vulnerable group of patients with respect to their quality of life and the burden of recurrent seizures. At our center, a large number of these patients undergo presurgical evaluation every year, which, in turn, may lead to an improved outcome following epilepsy surgery. However, candidates for surgery or patients who have had surgery were not investigated as separate subgroups in the present study. Surgery may affect the prevalence of psychiatric comorbidity (30–40% before surgery). A decrease in various psychiatric disorders has been demonstrated in recent studies, but de novo symptoms appearing after surgery have also been observed [30,31]. 4.5. Methodological considerations Limitations of the study include the fact that it was performed retrospectively based on the use of psychiatric comedication and data from medical records during a limited period of time. Medical records may lack data regarding other diagnoses and specific treatment of these disorders. Patients not receiving psychiatric pharmacotherapy were not included if the diagnosis was not yet made or if pharmacotherapy was regarded as unnecessary. An underestimation of psychiatric comorbid disorders may be the case in patients admitted to a referral center for epilepsy. The study material included a limited population of patients with refractory epilepsy, which is not representative of all patients with epilepsy. It is, however, regarded as representative for patients with refractory epilepsy in general, as this group of patients admitted to the referral center is recruited from the entire country. Furthermore, the population in Norway may be regarded as representative for other western European countries. However, the estimation of the utilization of drugs for psychiatric disorders in the total population may be overestimated because the numbers of patients who have received at least one prescription of these drugs are registered, and this might not reflect chronic use or a given diagnosis over time. 5. Conclusions Treatment of psychiatric comorbid disorders is an important issue in patients with refractory epilepsy. Pharmacological treatment of psychiatric comorbid disorders was employed in 13% of the patients. The lower prevalence of users of antidepressants and anxiolytics than in the general population points to undertreatment of this patient group. The results in the present study demonstrate that the treatment of patients with refractory epilepsy is complicated. The patients used two to eight concomitant CNS-active drugs, which calls for close monitoring of the potential for pharmacodynamic and pharmacokinetic interactions, and it challenges clinicians to achieve a less complex pharmacotherapy. Acknowledgments and disclosures We would like to acknowledge the following pharmacy students from the Dept. of Pharmacy and Biomedical Science, Oslo and Akershus University College of Applied Sciences for their participation in data
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