Epilepsy & Behavior 34 (2014) 116–119
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Safety of tianeptine use in patients with epilepsy Jangsup Moon 1, Keun-Hwa Jung 1, Jung-won Shin, Jung-Ah Lim, Jung-Ick Byun, Soon-Tae Lee, Kon Chu, Sang Kun Lee ⁎ Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea
a r t i c l e
i n f o
Article history: Received 12 November 2013 Revised 15 February 2014 Accepted 23 March 2014 Available online 14 April 2014 Keywords: Tianeptine Seizure frequency Antidepressant Patient with epilepsy
a b s t r a c t Depression is a frequent comorbidity in patients with epilepsy (PWE). However, it is often undertreated because of concerns of seizure exacerbation by antidepressant treatment. The effect of tianeptine on seizure frequency is not known as yet. Thus, we aimed to evaluate the influence of tianeptine on the seizure frequency in PWE. We retrospectively reviewed the medical records of PWE who received tianeptine between January 2006 and June 2013 at the Epilepsy Center of Seoul National University Hospital. Patients were excluded if the dose or type of antiepileptic drugs (AEDs) they took was altered at the start of tianeptine treatment or if the treatment period of tianeptine was b3 months. A total of 74 PWE were enrolled in our study (male: 32, mean age: 41.9 ± 14.5). Sixty-nine patients had localization-related epilepsy, and 5 had idiopathic generalized epilepsy (IGE). Mean seizure frequency during the 3-month period just after tianeptine exposure was compared with the baseline seizure frequency, which showed no change in 69 (93.2%) patients, decrease in 2 (2.7%) patients, and increase in 3 patients (4.1%). The type of epileptic syndrome, the baseline seizure frequency, and the number of coadministered AEDs did not influence the change in seizure frequency after tianeptine prescription. Change in seizure frequency did not differ between the patients given tianeptine as an additive antidepressant and those given tianeptine as a replacement antidepressant. Our data suggest that tianeptine can be prescribed safely to PWE with depression without increasing the seizure frequency regardless of the baseline severity of epilepsy. Tianeptine may be actively considered as a first-choice antidepressant or as an alternative antidepressant in PWE with depression. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Depression is at least 3 to 10 times more frequent in patients with epilepsy (PWE) than in the general population, and the prevalence of depression in PWE ranges from 20% to 62% [1]. Depression but not seizure frequency predicts the quality of life (QOL) in patients with refractory epilepsy, and more depression symptoms lead to poorer QOL [2]. However, depression is largely untreated in PWE [2,3]. One report showed that 43% of PWE with a major depressive episode were untreated [3]. Multiple factors have been suggested as the reason for the treatment gap [1], and concern about seizure exacerbation by antidepressants is a common cause of undertreatment in PWE [1,4]. Treatment with antidepressants, especially tricyclic agents (TCAs), has long been considered to aggravate seizures, and many antidepressants have been shown to lower seizure threshold in experimental
⁎ Corresponding author at: Department of Neurology, Seoul National University Hospital, 101 Daehangro, Chongro-Gu, Seoul 110-744, Republic of Korea. Tel.: +82 2 2072 2923; fax: +82 2 3672 7553. E-mail address: [email protected] (S.K. Lee). 1 The first two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.yebeh.2014.03.021 1525-5050/© 2014 Elsevier Inc. All rights reserved.
settings [5]. Incidence of seizures with TCAs at therapeutic doses is estimated to range from 0.4% to 2%. One major risk factor is the dose of the TCAs, and seizures tend to increase at higher doses of TCAs [5]. However, most of the previous data on seizure exacerbation were obtained from people without epilepsy and from cases of antidepressant overdose [5]. Increasing evidence suggests that newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin– norepinephrine reuptake inhibitors (SNRIs), rarely cause worsening of seizures in PWE [6]. At therapeutic doses of SSRIs and SNRIs, the incidence of seizures is generally lower than 0.4%, which is lower than that seen for TCAs [5]. Tianeptine is a new-generation antidepressant commonly used in the treatment of mild to moderate depressive disorders [7]. Although it is not available by prescription in the United States, United Kingdom, Canada, or Australia, it is commonly used in other European countries as well as in Asia and Latin America owing to its equivalent antidepressant properties and less adverse events compared with the classical antidepressants [8]. However, the effects of tianeptine on seizure frequency have not been studied in PWE. Here, we describe our retrospective study to evaluate the influence of tianeptine on seizure frequency in PWE.
J. Moon et al. / Epilepsy & Behavior 34 (2014) 116–119
117
2. Methods
2.4. Statistical analysis
2.1. Patient selection
The Wilcoxon rank-sum test or the Kruskal–Wallis test was used to compare the percentage changes in seizure frequency between each group. For statistical analysis, SPSS 20.0 for Windows (IBM Corp., Armonk, NY, USA) was used. A P value b 0.05 was considered significant.
We retrospectively reviewed the medical records of 137 PWE who started taking tianeptine at the Epilepsy Center of Seoul National University Hospital between January 2006 and June 2013. Sixty-three patients were excluded because the dose or type of antiepileptic drugs (AEDs) they took was altered at the start date of tianeptine treatment (45 patients) and the treatment period of tianeptine or follow-up period was shorter than 3 months (18 patients). Finally, 74 PWE were enrolled in our study. 2.2. Evaluation of the baseline seizure frequency Patients who were in complete seizure freedom for more than 1 year were classified into the 'group without seizures'. The rest of the patients were assigned to the group with persistent seizures. The latter group was subdivided into ‘patients with ≥1 seizure per month’ and ‘patients with b 1 seizure per month’ based on the mean seizure frequency during the last 1 year prior to tianeptine administration. 2.3. Evaluation of the seizure frequency after tianeptine administration We compared the 3-month seizure frequency just after tianeptine administration with the baseline seizure frequency. Baseline seizure frequency was evaluated by assessing the monthly seizure frequencies for the last 1 year before tianeptine prescription to factor in the within patient variability in seizure frequency over time. The change in seizure frequency after taking tianeptine was classified into 1 of 3 categories: increased, unchanged, and decreased. Increased seizure frequency was defined as follows: (1) if the monthly seizure frequency after tianeptine administration increased beyond the highest monthly seizure frequency during the previous 1 year and (2) if the patients went on to have secondarily generalized tonic–clonic seizures after starting tianeptine and only had complex or simple partial seizures beforehand. Decreased seizure frequency was considered if the monthly seizure frequency after tianeptine exposure was decreased to below 50% of the lowest monthly seizure frequency during the previous 1 year. The rest of the patients were assigned to the ‘unchanged’ seizure frequency group.
3. Results 3.1. Characteristics of the study subjects Seventy-four PWE were included in the study (male: 32, mean age: 41.9 ± 14.5). Sixty-nine patients had localization-related epilepsy (LRE), and 5 had idiopathic generalized epilepsy (IGE) (Table 1). None of the patients had a progressive neurodegenerative disease or a brain lesion requiring surgery. Twenty patients were seizure-free for more than a year, and 54 patients had persistent seizures during the last 1 year prior to tianeptine administration. Among the 'group with persistent seizures', 43 patients had ≥1 seizure per month, and 11 patients had b 1 seizure per month (Table 1). Among the patients with LRE, 19 patients were seizure-free, and 50 patients had persistent seizures (43 with ≥1 seizure per month and 7 with b1 seizure per month). Of the 5 patients with IGE, 1 patient was seizure-free, and 4 patients had persistent seizures (b1 seizure per month). Patients were taking 1 to 5 AEDs (N 4 AEDs, 8 patients; 3 AEDs, 19 patients; 2 AEDs, 22 patients; 1 AED, 25 patients) at the time of the first tianeptine prescription. Tianeptine was prescribed to treat mood disorder, anxiety disorder, and both in 61 patients, 7 patients, and 6 patients, respectively (Supplementary Table 1). All patients except 4 were given 25 mg of tianeptine per day (12.5 mg twice a day); 3 patients received 12.5 mg per day, and 1 received 37.5 mg per day. Eleven patients received tianeptine for periods between 3 and 6 months, and 63 patients took tianeptine for N6 months. In 51 patients, tianeptine was started as an initial antidepressant or as an additive antidepressant, and, in 23 patients, tianeptine was given in substitution for a prior antidepressant (Table 1). 3.2. Seizure frequency after tianeptine administration During the 3 months after tianeptine administration, when compared with the baseline frequency, seizure frequency remained unchanged in 69 patients (93.2%), decreased in 2 patients (2.7%), and
Table 1 Change in seizure frequency after tianeptine administration in patients with epilepsy.
Total Type of epileptic syndrome IGE LRE Baseline seizure frequency Seizure-free Persistent seizure ≥1 seizure per month b1 seizure per month Combined AEDs ≥4 AEDs 3 AEDs 2 AEDs 1 AED Relation to prior ADD In addition In substitution N6-Month treatment
Sz increased
Sz unchanged
Sz decreased
Total
3 (4.1%)
69 (93.2%)
2 (2.7%)
74
1 (20%) 4 (5.8%)
4 (80%) 63 (91.3%)
0 (0%) 2 (3.2%)
5 69
2 (10%) 1 (1.9%) 1 (2.3%) 0 (0%)
18 (90%) 51 (94.4%) 41 (95.3%) 10 (90.9%)
0 (0%) 2 (3.7%) 1 (2.3%) 1 (9.1%)
20 54 43 11
0 (0%) 1 (5.3%) 0 (0%) 2 (8%)
8 (100%) 18 (94.7%) 21 (95.5%) 22 (88%)
0 (0%) 0 (0%) 1 (4.5%) 1 (4%)
8 19 22 25
0 (0%) 3 (13.0%) 1 (1.6%)
50 (98.0%) 19 (82.6%) 60 (95.2%)
1 (2.0%) 1 (4.3%) 2 (3.2%)
51 23 63
P value 0.489a
0.083a
0.256a 0.608b
0.102a
Data represent the number (percentage) of patients. Abbreviations: Sz: seizure frequency, AED: antiepileptic drug, ADD: antidepressant drug, IGE: idiopathic generalized epilepsy, LRE: localization-related epilepsy. ‘In addition’: tianeptine was added to prior prescriptions (irrespective of prior ADD use). ‘In substitution’: tianeptine was given in substitution for a prior antidepressant drug. a Wilcoxon rank-sum test was performed. b Kruskal–Wallis test was performed.
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J. Moon et al. / Epilepsy & Behavior 34 (2014) 116–119
increased in 3 patients (4.1%). Among the 3 patients with increased seizure frequency, 2 were from the group without seizures, and 1 was from the group with persistent seizures (Table 1). Two patients from the group without seizures experienced complex partial seizures after tianeptine administration, although, in one patient, seizure was provoked by sleep deprivation during the mourning period after his mother's death. One patient in the group with persistent seizures experienced the same type of seizure from the baseline but with increased frequency (Supplementary Table 2). Among the 63 patients who received tianeptine for N 6 months, the seizure frequency at 6 months remained unchanged in 60 patients (95.2%), decreased in 2 patients (3.2%), and increased in 1 patient (1.6%). The change in seizure frequency was not different according to the type of epilepsy syndrome (P = 0.489, Table 1): IGE (1 increased, 4 unchanged) and LRE (2 increased, 65 unchanged, 2 decreased). The change in seizure frequency was not different whether the seizure was persistent or absent at the baseline (P = 0.083, Table 1, Fig. 1A): seizure-free (n = 20; 2 increased, 18 unchanged) and persistent seizure (n = 54; 1 increased, 51 unchanged, 2 decreased). The difference of baseline seizure frequency within the group with persistent seizures did not affect the impact of tianeptine on seizure frequency (P = 0.256, Table 1): ≥1 seizure per month (n = 43: 1 increased, 41 unchanged, 1 decreased) and b1 seizure per month (n = 11; 10 unchanged, 1 decreased). The change in seizure frequency did not differ according to the number of AEDs patients were taking (P = 0.608, Table 1, Fig. 1B): ≥4 AEDs (n = 8; 8 unchanged), 3 AEDs (n = 19; 1 increased, 18 unchanged), 2 AEDs (n = 22; 21 unchanged, 1 decreased), and 1 AED (n = 25; 2 increased, 22 unchanged, 1 decreased). The change in seizure frequency did not differ significantly between patients given tianeptine in addition to prior prescriptions and those given tianeptine as an alternative to a previously used antidepressant (P = 0.102, Table 1, Fig. 1C): as an additional treatment (n = 51; 50 unchanged, 1 decreased) and as an alternative treatment (n = 23; 3 increased, 19 unchanged, 1 decreased). 4. Discussion To our knowledge, this is the first study to assess the effect of tianeptine on seizure frequency in PWE. Our data suggest that tianeptine can be safely prescribed to PWE with depression without increasing seizure frequency. The baseline severity of epilepsy or temporal relationship with other antidepressants did not affect the safety of tianeptine. In our study, the 3-month seizure frequency in most patients (93.2%) did not change after tianeptine administration, and only 4.1% of patients
experienced seizure aggravation after receiving tianeptine. Within the group without seizures, 2 out of 20 patients (10%) experienced seizures after taking tianeptine which can be regarded as a substantial proportion. However, one patient demonstrated brief LOC which was provoked by sleep deprivation after his mother's death. Considering the small number of patients in the group without seizures and the presence of an obvious aggravating factor in one patient, we contend that the effect of tianeptine on seizure aggravation is uncertain. In the group with persistent seizures, while only 1 patient (4.4%) experienced worsening of seizure, seizure frequency even decreased in 2 patients after tianeptine use. Overall, we concluded that tianeptine rarely causes an increase in seizure frequency. This safety profile was consistent in the 63 patients who received tianeptine for N6 months. We attempted to evaluate whether the effect of tianeptine on seizure frequency was related to the baseline severity of epilepsy. The change in seizure frequency after tianeptine treatment was not different between patients with seizure freedom and those with persistent seizures. Also, there was no difference between patients with ≥ 1 seizure per month and patients with b 1 seizure per month. We also regarded the large number of AEDs given to patients as indirect evidence of intractability of the epilepsy. However, the change in seizure frequency did not differ according to the number of AEDs patients were taking. Therefore, we suggest that tianeptine is a safe drug of choice in PWE with depression regardless of the baseline severity of epilepsy. We also investigated whether the temporal relationship of the administration of tianeptine and other antidepressants influenced the seizure frequency. We believe that this is an important issue because it is known that many antidepressants influence seizure threshold [9] and changes in the administration of other antidepressants may influence seizure frequency. We dichotomized the patients into 2 groups. One group included patients who received tianeptine as an initial or additive antidepressant, and the other group included patients who received tianeptine as a replacement for a prior antidepressant. The change in seizure frequency did not differ between these two groups. Thus, we conclude that tianeptine can be prescribed safely as a first-choice antidepressant and as an additional or alternative antidepressant to PWE with depression without aggravating seizure frequency. Tianeptine is an antidepressant agent that has a novel neurochemical profile and numerous clinical advantages. In contrast to most antidepressants, tianeptine increases serotonin uptake in the brain and reduces stress-induced atrophy of neuronal dendrites [8]. Clinically, tianeptine is effective in reducing symptoms of mild to moderate depression, and it also has excellent anxiolytic efficacy [8]. Although the efficacy is equivalent to that of classical antidepressants, tianeptine
Fig. 1. Change in seizure frequency after administration of tianeptine. The data are grouped by the baseline seizure frequency (A), the number of antiepileptic drugs (AEDs) patients were taking (B), and the temporal relation of tianeptine to prior antidepressant drugs (ADDs) (C). Change in seizure frequency did not differ between groups on each comparison (A, P = 0.083; B, P = 0.608; C, P = 0.102).
J. Moon et al. / Epilepsy & Behavior 34 (2014) 116–119
is generally well tolerated with minimal sedation or cognitive impairment [8,10]. Moreover, it has a favorable pharmacokinetic profile and low chance of drug–drug interactions [8], which makes it suitable for patients taking multiple drugs. In addition, recent studies have demonstrated the anticonvulsant effect of tianeptine in animal epilepsy models [7,11,12]. The anticonvulsant effect of tianeptine in PWE needs to be investigated in the near future. Our study has some limitations. First, this study includes only a small number of patients with IGE. Because of the small sample size, it is difficult to arrive at a conclusion about the effect of tianeptine on seizure frequency in patients with IGE. It needs to be reevaluated in the future with a larger number of patients with IGE. Second, we could not evaluate the dose-dependent effect of tianeptine on seizure frequency because most of the patients received 25 mg per day which is the regular therapeutic dose [8]. The influence of higher doses of tianeptine on seizure frequency needs to be evaluated. In conclusion, tianeptine can be administered safely without aggravating seizure frequency in PWE who experience depression and anxiety. We suggest that tianeptine may be actively considered as a first-choice antidepressant or as an alternative antidepressant in PWE with depression. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.yebeh.2014.03.021. Acknowledgments This study was supported by the Mid-career Researcher Program through the NRF grant funded by the MEST (NRF-2011-0016634). S.K.L. was supported by Seoul National University Hospital (0420130580).
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Conflict of interest statement None of the authors has any conflict of interest to disclose.
References [1] Cotterman-Hart S. Depression in epilepsy: why aren't we treating? Epilepsy Behav 2010;19:419–21. [2] Boylan L, Flint L, Labovitz D, Jackson S, Starner K, Devinsky O. Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology 2004;62:258–61. [3] Wiegartz P, Seidenberg M, Woodard A, Gidal B, Hermann B. Co-morbid psychiatric disorder in chronic epilepsy: recognition and etiology of depression. Neurology 1999;53:S3–8. [4] Barry JJ, Ettinger AB, Friel P, Gilliam FG, Harden CL, Hermann B, et al. Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders. Epilepsy Behav 2008;13:S1–S29. [5] Montgomery S. Antidepressants and seizures: emphasis on newer agents and clinical implications. Int J Clin Pract 2005;59:1435–40. [6] Cardamone L, Salzberg M, O'Brien T, Jones N. Antidepressant therapy in epilepsy: can treating the comorbidities affect the underlying disorder? Br J Pharmacol 2013;168:1531–54. [7] Borowicz KK, Banach M, Piskorska B, Czuczwar SaJ. Effect of acute and chronic tianeptine on the action of classical antiepileptics in the mouse maximal electroshock model. Pharmacol Rep 2013;65:379–88. [8] Wagstaff AJ, Ormrod D, Spencer CM. Tianeptine. CNS Drugs 2001;15:231–59. [9] Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R. Effects of psychotropic drugs on seizure threshold. Drug Saf 2002;25:91–110. [10] Kasper S, McEwen BS. Neurobiological and clinical effects of the antidepressant tianeptine. CNS Drugs 2008;22:15–26. [11] Ceyhan M, Kayir H, Uzbay IT. Investigation of the effects of tianeptine and fluoxetine on pentylenetetrazole-induced seizures in rats. J Psychiatr Res 2005;39:191–6. [12] Uzbay TI, Kayir H, Ceyhan M. Effects of tianeptine on onset time of pentylenetetrazole-induced seizures in mice: possible role of adenosine A1 receptors. Neuropsychopharmacology 2006;32:412–6.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Safety of tianeptine use in patients with epilepsy Jangsup Moon 1, Keun-Hwa Jung 1, Jung-won Shin, Jung-Ah Lim, Jung-Ick Byun, Soon-Tae Lee, Kon Chu, Sang Kun Lee ⁎ Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea
a r t i c l e
i n f o
Article history: Received 12 November 2013 Revised 15 February 2014 Accepted 23 March 2014 Available online 14 April 2014 Keywords: Tianeptine Seizure frequency Antidepressant Patient with epilepsy
a b s t r a c t Depression is a frequent comorbidity in patients with epilepsy (PWE). However, it is often undertreated because of concerns of seizure exacerbation by antidepressant treatment. The effect of tianeptine on seizure frequency is not known as yet. Thus, we aimed to evaluate the influence of tianeptine on the seizure frequency in PWE. We retrospectively reviewed the medical records of PWE who received tianeptine between January 2006 and June 2013 at the Epilepsy Center of Seoul National University Hospital. Patients were excluded if the dose or type of antiepileptic drugs (AEDs) they took was altered at the start of tianeptine treatment or if the treatment period of tianeptine was b3 months. A total of 74 PWE were enrolled in our study (male: 32, mean age: 41.9 ± 14.5). Sixty-nine patients had localization-related epilepsy, and 5 had idiopathic generalized epilepsy (IGE). Mean seizure frequency during the 3-month period just after tianeptine exposure was compared with the baseline seizure frequency, which showed no change in 69 (93.2%) patients, decrease in 2 (2.7%) patients, and increase in 3 patients (4.1%). The type of epileptic syndrome, the baseline seizure frequency, and the number of coadministered AEDs did not influence the change in seizure frequency after tianeptine prescription. Change in seizure frequency did not differ between the patients given tianeptine as an additive antidepressant and those given tianeptine as a replacement antidepressant. Our data suggest that tianeptine can be prescribed safely to PWE with depression without increasing the seizure frequency regardless of the baseline severity of epilepsy. Tianeptine may be actively considered as a first-choice antidepressant or as an alternative antidepressant in PWE with depression. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Depression is at least 3 to 10 times more frequent in patients with epilepsy (PWE) than in the general population, and the prevalence of depression in PWE ranges from 20% to 62% [1]. Depression but not seizure frequency predicts the quality of life (QOL) in patients with refractory epilepsy, and more depression symptoms lead to poorer QOL [2]. However, depression is largely untreated in PWE [2,3]. One report showed that 43% of PWE with a major depressive episode were untreated [3]. Multiple factors have been suggested as the reason for the treatment gap [1], and concern about seizure exacerbation by antidepressants is a common cause of undertreatment in PWE [1,4]. Treatment with antidepressants, especially tricyclic agents (TCAs), has long been considered to aggravate seizures, and many antidepressants have been shown to lower seizure threshold in experimental
⁎ Corresponding author at: Department of Neurology, Seoul National University Hospital, 101 Daehangro, Chongro-Gu, Seoul 110-744, Republic of Korea. Tel.: +82 2 2072 2923; fax: +82 2 3672 7553. E-mail address: [email protected] (S.K. Lee). 1 The first two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.yebeh.2014.03.021 1525-5050/© 2014 Elsevier Inc. All rights reserved.
settings [5]. Incidence of seizures with TCAs at therapeutic doses is estimated to range from 0.4% to 2%. One major risk factor is the dose of the TCAs, and seizures tend to increase at higher doses of TCAs [5]. However, most of the previous data on seizure exacerbation were obtained from people without epilepsy and from cases of antidepressant overdose [5]. Increasing evidence suggests that newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin– norepinephrine reuptake inhibitors (SNRIs), rarely cause worsening of seizures in PWE [6]. At therapeutic doses of SSRIs and SNRIs, the incidence of seizures is generally lower than 0.4%, which is lower than that seen for TCAs [5]. Tianeptine is a new-generation antidepressant commonly used in the treatment of mild to moderate depressive disorders [7]. Although it is not available by prescription in the United States, United Kingdom, Canada, or Australia, it is commonly used in other European countries as well as in Asia and Latin America owing to its equivalent antidepressant properties and less adverse events compared with the classical antidepressants [8]. However, the effects of tianeptine on seizure frequency have not been studied in PWE. Here, we describe our retrospective study to evaluate the influence of tianeptine on seizure frequency in PWE.
J. Moon et al. / Epilepsy & Behavior 34 (2014) 116–119
117
2. Methods
2.4. Statistical analysis
2.1. Patient selection
The Wilcoxon rank-sum test or the Kruskal–Wallis test was used to compare the percentage changes in seizure frequency between each group. For statistical analysis, SPSS 20.0 for Windows (IBM Corp., Armonk, NY, USA) was used. A P value b 0.05 was considered significant.
We retrospectively reviewed the medical records of 137 PWE who started taking tianeptine at the Epilepsy Center of Seoul National University Hospital between January 2006 and June 2013. Sixty-three patients were excluded because the dose or type of antiepileptic drugs (AEDs) they took was altered at the start date of tianeptine treatment (45 patients) and the treatment period of tianeptine or follow-up period was shorter than 3 months (18 patients). Finally, 74 PWE were enrolled in our study. 2.2. Evaluation of the baseline seizure frequency Patients who were in complete seizure freedom for more than 1 year were classified into the 'group without seizures'. The rest of the patients were assigned to the group with persistent seizures. The latter group was subdivided into ‘patients with ≥1 seizure per month’ and ‘patients with b 1 seizure per month’ based on the mean seizure frequency during the last 1 year prior to tianeptine administration. 2.3. Evaluation of the seizure frequency after tianeptine administration We compared the 3-month seizure frequency just after tianeptine administration with the baseline seizure frequency. Baseline seizure frequency was evaluated by assessing the monthly seizure frequencies for the last 1 year before tianeptine prescription to factor in the within patient variability in seizure frequency over time. The change in seizure frequency after taking tianeptine was classified into 1 of 3 categories: increased, unchanged, and decreased. Increased seizure frequency was defined as follows: (1) if the monthly seizure frequency after tianeptine administration increased beyond the highest monthly seizure frequency during the previous 1 year and (2) if the patients went on to have secondarily generalized tonic–clonic seizures after starting tianeptine and only had complex or simple partial seizures beforehand. Decreased seizure frequency was considered if the monthly seizure frequency after tianeptine exposure was decreased to below 50% of the lowest monthly seizure frequency during the previous 1 year. The rest of the patients were assigned to the ‘unchanged’ seizure frequency group.
3. Results 3.1. Characteristics of the study subjects Seventy-four PWE were included in the study (male: 32, mean age: 41.9 ± 14.5). Sixty-nine patients had localization-related epilepsy (LRE), and 5 had idiopathic generalized epilepsy (IGE) (Table 1). None of the patients had a progressive neurodegenerative disease or a brain lesion requiring surgery. Twenty patients were seizure-free for more than a year, and 54 patients had persistent seizures during the last 1 year prior to tianeptine administration. Among the 'group with persistent seizures', 43 patients had ≥1 seizure per month, and 11 patients had b 1 seizure per month (Table 1). Among the patients with LRE, 19 patients were seizure-free, and 50 patients had persistent seizures (43 with ≥1 seizure per month and 7 with b1 seizure per month). Of the 5 patients with IGE, 1 patient was seizure-free, and 4 patients had persistent seizures (b1 seizure per month). Patients were taking 1 to 5 AEDs (N 4 AEDs, 8 patients; 3 AEDs, 19 patients; 2 AEDs, 22 patients; 1 AED, 25 patients) at the time of the first tianeptine prescription. Tianeptine was prescribed to treat mood disorder, anxiety disorder, and both in 61 patients, 7 patients, and 6 patients, respectively (Supplementary Table 1). All patients except 4 were given 25 mg of tianeptine per day (12.5 mg twice a day); 3 patients received 12.5 mg per day, and 1 received 37.5 mg per day. Eleven patients received tianeptine for periods between 3 and 6 months, and 63 patients took tianeptine for N6 months. In 51 patients, tianeptine was started as an initial antidepressant or as an additive antidepressant, and, in 23 patients, tianeptine was given in substitution for a prior antidepressant (Table 1). 3.2. Seizure frequency after tianeptine administration During the 3 months after tianeptine administration, when compared with the baseline frequency, seizure frequency remained unchanged in 69 patients (93.2%), decreased in 2 patients (2.7%), and
Table 1 Change in seizure frequency after tianeptine administration in patients with epilepsy.
Total Type of epileptic syndrome IGE LRE Baseline seizure frequency Seizure-free Persistent seizure ≥1 seizure per month b1 seizure per month Combined AEDs ≥4 AEDs 3 AEDs 2 AEDs 1 AED Relation to prior ADD In addition In substitution N6-Month treatment
Sz increased
Sz unchanged
Sz decreased
Total
3 (4.1%)
69 (93.2%)
2 (2.7%)
74
1 (20%) 4 (5.8%)
4 (80%) 63 (91.3%)
0 (0%) 2 (3.2%)
5 69
2 (10%) 1 (1.9%) 1 (2.3%) 0 (0%)
18 (90%) 51 (94.4%) 41 (95.3%) 10 (90.9%)
0 (0%) 2 (3.7%) 1 (2.3%) 1 (9.1%)
20 54 43 11
0 (0%) 1 (5.3%) 0 (0%) 2 (8%)
8 (100%) 18 (94.7%) 21 (95.5%) 22 (88%)
0 (0%) 0 (0%) 1 (4.5%) 1 (4%)
8 19 22 25
0 (0%) 3 (13.0%) 1 (1.6%)
50 (98.0%) 19 (82.6%) 60 (95.2%)
1 (2.0%) 1 (4.3%) 2 (3.2%)
51 23 63
P value 0.489a
0.083a
0.256a 0.608b
0.102a
Data represent the number (percentage) of patients. Abbreviations: Sz: seizure frequency, AED: antiepileptic drug, ADD: antidepressant drug, IGE: idiopathic generalized epilepsy, LRE: localization-related epilepsy. ‘In addition’: tianeptine was added to prior prescriptions (irrespective of prior ADD use). ‘In substitution’: tianeptine was given in substitution for a prior antidepressant drug. a Wilcoxon rank-sum test was performed. b Kruskal–Wallis test was performed.
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increased in 3 patients (4.1%). Among the 3 patients with increased seizure frequency, 2 were from the group without seizures, and 1 was from the group with persistent seizures (Table 1). Two patients from the group without seizures experienced complex partial seizures after tianeptine administration, although, in one patient, seizure was provoked by sleep deprivation during the mourning period after his mother's death. One patient in the group with persistent seizures experienced the same type of seizure from the baseline but with increased frequency (Supplementary Table 2). Among the 63 patients who received tianeptine for N 6 months, the seizure frequency at 6 months remained unchanged in 60 patients (95.2%), decreased in 2 patients (3.2%), and increased in 1 patient (1.6%). The change in seizure frequency was not different according to the type of epilepsy syndrome (P = 0.489, Table 1): IGE (1 increased, 4 unchanged) and LRE (2 increased, 65 unchanged, 2 decreased). The change in seizure frequency was not different whether the seizure was persistent or absent at the baseline (P = 0.083, Table 1, Fig. 1A): seizure-free (n = 20; 2 increased, 18 unchanged) and persistent seizure (n = 54; 1 increased, 51 unchanged, 2 decreased). The difference of baseline seizure frequency within the group with persistent seizures did not affect the impact of tianeptine on seizure frequency (P = 0.256, Table 1): ≥1 seizure per month (n = 43: 1 increased, 41 unchanged, 1 decreased) and b1 seizure per month (n = 11; 10 unchanged, 1 decreased). The change in seizure frequency did not differ according to the number of AEDs patients were taking (P = 0.608, Table 1, Fig. 1B): ≥4 AEDs (n = 8; 8 unchanged), 3 AEDs (n = 19; 1 increased, 18 unchanged), 2 AEDs (n = 22; 21 unchanged, 1 decreased), and 1 AED (n = 25; 2 increased, 22 unchanged, 1 decreased). The change in seizure frequency did not differ significantly between patients given tianeptine in addition to prior prescriptions and those given tianeptine as an alternative to a previously used antidepressant (P = 0.102, Table 1, Fig. 1C): as an additional treatment (n = 51; 50 unchanged, 1 decreased) and as an alternative treatment (n = 23; 3 increased, 19 unchanged, 1 decreased). 4. Discussion To our knowledge, this is the first study to assess the effect of tianeptine on seizure frequency in PWE. Our data suggest that tianeptine can be safely prescribed to PWE with depression without increasing seizure frequency. The baseline severity of epilepsy or temporal relationship with other antidepressants did not affect the safety of tianeptine. In our study, the 3-month seizure frequency in most patients (93.2%) did not change after tianeptine administration, and only 4.1% of patients
experienced seizure aggravation after receiving tianeptine. Within the group without seizures, 2 out of 20 patients (10%) experienced seizures after taking tianeptine which can be regarded as a substantial proportion. However, one patient demonstrated brief LOC which was provoked by sleep deprivation after his mother's death. Considering the small number of patients in the group without seizures and the presence of an obvious aggravating factor in one patient, we contend that the effect of tianeptine on seizure aggravation is uncertain. In the group with persistent seizures, while only 1 patient (4.4%) experienced worsening of seizure, seizure frequency even decreased in 2 patients after tianeptine use. Overall, we concluded that tianeptine rarely causes an increase in seizure frequency. This safety profile was consistent in the 63 patients who received tianeptine for N6 months. We attempted to evaluate whether the effect of tianeptine on seizure frequency was related to the baseline severity of epilepsy. The change in seizure frequency after tianeptine treatment was not different between patients with seizure freedom and those with persistent seizures. Also, there was no difference between patients with ≥ 1 seizure per month and patients with b 1 seizure per month. We also regarded the large number of AEDs given to patients as indirect evidence of intractability of the epilepsy. However, the change in seizure frequency did not differ according to the number of AEDs patients were taking. Therefore, we suggest that tianeptine is a safe drug of choice in PWE with depression regardless of the baseline severity of epilepsy. We also investigated whether the temporal relationship of the administration of tianeptine and other antidepressants influenced the seizure frequency. We believe that this is an important issue because it is known that many antidepressants influence seizure threshold [9] and changes in the administration of other antidepressants may influence seizure frequency. We dichotomized the patients into 2 groups. One group included patients who received tianeptine as an initial or additive antidepressant, and the other group included patients who received tianeptine as a replacement for a prior antidepressant. The change in seizure frequency did not differ between these two groups. Thus, we conclude that tianeptine can be prescribed safely as a first-choice antidepressant and as an additional or alternative antidepressant to PWE with depression without aggravating seizure frequency. Tianeptine is an antidepressant agent that has a novel neurochemical profile and numerous clinical advantages. In contrast to most antidepressants, tianeptine increases serotonin uptake in the brain and reduces stress-induced atrophy of neuronal dendrites [8]. Clinically, tianeptine is effective in reducing symptoms of mild to moderate depression, and it also has excellent anxiolytic efficacy [8]. Although the efficacy is equivalent to that of classical antidepressants, tianeptine
Fig. 1. Change in seizure frequency after administration of tianeptine. The data are grouped by the baseline seizure frequency (A), the number of antiepileptic drugs (AEDs) patients were taking (B), and the temporal relation of tianeptine to prior antidepressant drugs (ADDs) (C). Change in seizure frequency did not differ between groups on each comparison (A, P = 0.083; B, P = 0.608; C, P = 0.102).
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is generally well tolerated with minimal sedation or cognitive impairment [8,10]. Moreover, it has a favorable pharmacokinetic profile and low chance of drug–drug interactions [8], which makes it suitable for patients taking multiple drugs. In addition, recent studies have demonstrated the anticonvulsant effect of tianeptine in animal epilepsy models [7,11,12]. The anticonvulsant effect of tianeptine in PWE needs to be investigated in the near future. Our study has some limitations. First, this study includes only a small number of patients with IGE. Because of the small sample size, it is difficult to arrive at a conclusion about the effect of tianeptine on seizure frequency in patients with IGE. It needs to be reevaluated in the future with a larger number of patients with IGE. Second, we could not evaluate the dose-dependent effect of tianeptine on seizure frequency because most of the patients received 25 mg per day which is the regular therapeutic dose [8]. The influence of higher doses of tianeptine on seizure frequency needs to be evaluated. In conclusion, tianeptine can be administered safely without aggravating seizure frequency in PWE who experience depression and anxiety. We suggest that tianeptine may be actively considered as a first-choice antidepressant or as an alternative antidepressant in PWE with depression. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.yebeh.2014.03.021. Acknowledgments This study was supported by the Mid-career Researcher Program through the NRF grant funded by the MEST (NRF-2011-0016634). S.K.L. was supported by Seoul National University Hospital (0420130580).
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Conflict of interest statement None of the authors has any conflict of interest to disclose.
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