YEBEH-04718; No of Pages 5 Epilepsy & Behavior xxx (2016) xxx–xxx
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Review
Proconvulsant effects of antidepressants — What is the current evidence? Cecilie Johannessen Landmark a,b,c,⁎, Oliver Henning b, Svein I. Johannessen b,c a b c
Dept. of Life Sciences and Health, Programme for Pharmacy, Faculty of Health Science, Oslo and Akershus University College of Applied Sciences, Oslo, Norway The National Center for Epilepsy, Sandvika, Oslo University Hospital, Oslo, Norway Department of Pharmacology, Oslo University Hospital, Oslo, Norway
a r t i c l e
i n f o
Article history: Revised 23 January 2016 Accepted 25 January 2016 Available online xxxx Keywords: Antidepressant drugs Proconvulsant Seizures Drug safety
a b s t r a c t Antidepressant drugs may have proconvulsant effects. Psychiatric comorbidity in epilepsy is common. Prescribers might be reluctant to initiate treatment with antidepressants in fear of seizure aggravation. The purpose of this review was to focus upon the current evidence for proconvulsant effects of antidepressants and possible clinical implications. Most antidepressants are regarded as safe and may be used in patients with epilepsy, such as the newer serotonin and/or noradrenaline reuptake inhibitors. Four older drugs should, however, be avoided or used with caution; amoxapine, bupropion, clomipramine and maprotiline. Proconvulsant effects are concentration-related. Optimization of drug treatment includes considerations of pharmacokinetic variability to avoid high serum concentrations of the most proconvulsant antidepressants. The risk of seizures is regarded as small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Antidepressants drugs have been used to treat symptoms of depression since they were introduced in the late 1950s. They consist of a broad range of drugs, all affecting the neurochemical balance of monoamine neurotransmitters in the central nervous system. Some antidepressants have been demonstrated to have proconvulsant effects. In the present review, the main focus will be on patients with epilepsy, since they are most vulnerable to have seizures because of a lower seizure threshold than the population as a whole. Seizures caused by excessive intake of antidepressants or overdose will, however, be briefly described in general. A prevalence rate of depression in epilepsy between 6 and 30% has been shown with various methods [1–5]. Patients with epilepsy and comorbid psychiatric disorders form a large group. Antiepileptic drugs have various beneficial pharmacological effects in psychiatric disorders and are increasingly used in such indications [6–8]. Extensive polypharmacy might lead to interactions and adverse effects [4,9]. Studies have shown that psychiatric disorders in these patients may be underdiagnosed and undertreated [10,11]. A recent survey showed that the main barrier in treating depression in patients with epilepsy is the fear of an increased seizure frequency, according to 52% of primary care physicians, and even 10% of neurologists [12]. Updated knowledge of which antidepressants may have proconvulsant effects and, thus, should be avoided is, therefore, of utmost importance.
⁎ Corresponding author at: Dept. of Life Sciences and Health, Programme for Pharmacy, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Pilestredet 50, N-0167 Oslo, Norway. Tel.: +47 22452360; fax: +47 22452335. E-mail address: [email protected] (C. Johannessen Landmark).
The purpose of the present review was to focus upon the current evidence of possible proconvulsant effects of antidepressants and their clinical implications, in order to help prescribers decide which antidepressants should be avoided in patients with epilepsy. 1.1. Description of antidepressants Antidepressant drugs are defined according to the classification of drugs based upon the Anatomical Therapeutic Chemical classification (ATC)-codes where antiepileptic drugs (AEDs) are defined as N06A [13]. Classification of antidepressants is summarized in Table 1. The main categories include the newer selective serotonin reuptake inhibitors (SSRIs), the older nonselective monoamine reuptake inhibitors or tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, selective or nonselective for MAOA, and other antidepressants. They also include the newer selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, duloxetine, reboxetine). Their possible propensities to cause proconvulsant effects will be described. 1.2. Search criteria and literature review The present review is based upon recently published articles identified by searches in PubMed and Google Scholar, in addition to the authors' files. Selected publications of interest were included (1982–2015) with emphasis on the last five years. The search period was to January 2016. Peer-reviewed articles or abstracts on the topic in recognized international journals in English were included, whereas non-English articles were disregarded. Both preclinical and clinical and acute and chronic studies were regarded as relevant, as well as the use of various animal models. Review articles giving a broad and updated overview
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Please cite this article as: Johannessen Landmark C, et al, Proconvulsant effects of antidepressants — What is the current evidence? Epilepsy Behav (2016), http://dx.doi.org/10.1016/j.yebeh.2016.01.029
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Table 1 Classification of antidepressants and their propensity to cause seizures. Antidepressant drug classes
Drug examples
Drugs with propensity to cause seizures and metabolic pathway
Nonselective monoamine reuptake inhibitors (TCA)
Amitriptyline, doxepin, nortriptyline, trimipramine
Selective serotonin reuptake inhibitors (SSRI)
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline Venlafaxine, reboxetine, duloxetine
Clomipramine (CYP1A2, 3A4, 2D6) None
Selective noradrenaline or noradrenaline/serotonin reuptake inhibitors (SNRI) Monoamine oxidase inhibitors (MAO), nonselective Monoamine oxidase A inhibitors (MAOA) Other antidepressants
Moclobemide Mianserin, mirtazapine
None Maprotiline (CYP2D6), amoxapine (CYP2D6) None Bupropion (CYP2B6), inhibitor of CYP2D6
The classification of antidepressants is based on the ATC classification system [13].
regarding possible proconvulsant effects of antidepressants were also included. General reviews with a scope besides proconvulsant effects were disregarded. During the searches, the key words antidepressants (specific searches for amoxapine, bupropion, clomipramine, maprotiline, mianserin), anticonvulsant, antiepileptic drugs, clinical study, dose, drug safety, interactions, mice, overdose, preclinical study, proconvulsant, SNRI, SSRI, rat, therapeutic drug monitoring, tricyclic antidepressant, and zebrafish were used, and the various key words were combined. 2. Proconvulsant effects of antidepressants
GABAergic and excitatory glutamatergic neurotransmission with increase in glutamatergic activation and, thus, excessive calcium influx, initiating intracellular processes. The underlying mechanisms are not clear [14]. In a recent review, the role of serotonin in the control of neuronal excitability, epileptogenesis, and seizure propagation is emphasized, and various effects are observed through modulation of different subtypes of 5-HT receptors throughout the brain [15]. Noradrenergic and serotonergic effects of antidepressants seem to be anticonvulsant in therapeutic doses, whereas supratherapeutic doses or serum concentrations may activate other neurochemical pathways that may culminate in seizures [16–18].
2.1. Neurochemical background 2.2. Preclinical evidence of specific drugs The monoamines are the main neurotransmitters that are affected by antidepressants. It is well known that it takes several weeks to observe clinical effects of these drugs, pointing to a long-term change in establishing a neurochemical balance within these neuronal networks. The main targets for pharmacological action of antidepressants vs AEDs in the synapses are shown in Fig. 1. Antidepressants may disturb the neuronal balance and control of excitability, leading to seizures. Seizures may occur as a consequence of a misbalance between inhibitory
When reviewing the literature, four antidepressants, in particular, appear to have most pronounced proconvulsant effects, namely the tricyclic antidepressant clomipramine, the unselective MAO-inhibitors amoxapine and maprotiline, and the atypical antidepressant bupropion, the latter being a noradrenaline and dopamine reuptake inhibitor (Table 1). For all other antidepressants, the seizure risk is regarded as low.
Fig. 1. Mechanisms of action of antidepressants vs antiepileptic drugs in the synapses.
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It is difficult to extrapolate results from in vitro data to clinical practice, as variability in methodology and complex effects might be impossible to predict [19]. In addition, the experimental evidence for the proconvulsant effects of several antidepressants, including clomipramine, amoxapine, and bupropion, is based upon early studies in animals where relatively high doses were administered. For example, in the study by Peterson et al. [20], clomipramine was administered at doses of 20–40 mg/kg, amoxapine at 20–40 mg/kg, or desipramine at 10– 20 mg/kg, which all are far above therapeutic doses. Acute vs chronic effects of the seizure threshold may vary, and chronic effects may have a more pronounced effect than acute effects. Chronic administration of clomipramine, amoxapine, or desimipramine in rats for twenty days demonstrated an increased susceptibility for the animals to have seizures than with mianserin, whereas no effects were seen after acute administration of one dose [20]. This was explained based on the prolonged effects of these antidepressants on noradrenergic balance that would affect excitability. It has been suggested that the proconvulsant liability of antidepressants may be both concentrationand model-dependent, as demonstrated in a study with seizures in mice and zebrafish with drugs as reboxetine and bupropion [21]. The mouse model with pilocarpine-induced seizures was more sensitive to lowering of the seizure threshold than pentylenetetrazoleinduced seizures in both mice and zebrafish [21]. In another recent study, electroencephalographical (EEG) measurement in the fentanyl/ etomidate-anesthetized beagle (FEAB) model was implemented in order to detect burst suppression and/or seizure development caused by proconvulsant compounds as bupropion and showed to be suitable in pharmacological studies [22]. 2.3. Clinical evidence of specific drugs Documentation from randomized controlled trials regarding the seizure frequency when treating patients with epilepsy with antidepressants is sparse. As described in the section of preclinical evidence, for most antidepressants, the risk of seizures is small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy. The newer classes of antidepressants, SSRIs and SNRIs, are safe for people with epilepsy, and they seem to obtain therapeutic responses independently of seizure frequency. These drugs appear to have a potential for anticonvulsant effects rather than proconvulsant effects [23–25]. Most information comes from the nonepileptic population from premarketing trials where epilepsy often is an exclusion criterion or from postmarketing analyses where the conditions and data are much more variable. In the nonepileptic population, an increased seizure risk has, among others, been associated with high serum concentrations, which can be due to slow metabolism and a rapid dose titration [14,26–29]. This is supported by the fact that some antidepressants may have anticonvulsant properties when used in low dosages while they are proconvulsant in higher dosages [19]. Clomipramine, maprotiline, amoxapine, and bupropion are especially regarded to have a high risk to increase seizures when used in patients with epilepsy [28], with increasing risk in intentional or accidental overdose [18]. For mianserin, however, no further clinical evidence was found. The available data in this context must be interpreted in relation with the fact that there is a bidirectional relationship between depression and epilepsy. People with epilepsy are at increased risk for depression. On the other hand, people with psychiatric disorders, including depression, have a two- to sevenfold risk of developing seizures/epilepsy at some stage [30,31]. Therefore, the occurrence of seizures in a patient with depression may be an expression of the natural course of the disease, rather than an adverse effect of antidepressant therapy [32]. 2.3.1. Clomipramine This drug is no longer as clinically relevant as an antidepressant since the majority of use of antidepressants consists of newer and
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more selective drugs (SSRIs). A possible proconvulsant effect of clomipramine has, however, only been demonstrated in supratherapeutic doses in animals (20–40 mg/kg) [20]. Therapeutic doses are usually in the order of 50 and up to 150 mg/day. But clomipramine is still used to some degree, mainly for the indication of obsessive–compulsive disorder (OCD). In a review from the US Food and Drug Administration (FDA) phase II and III studies for psychopharmacological drugs with regard to seizures, Alper et al. [23] found clomipramine used for OCD to have the highest risk (0.7%) among the included drugs. The drug has an intermediate (5%–10%) risk for overdose-induced seizures [18]. If possible, it should be avoided in patients with epilepsy. 2.3.2. Amoxapine Various case reports describe seizures associated with amoxapine treatment also within usual dosage ranges, mainly from the 1980s [33, 34]. The drug has a high (about 30%) risk for overdose-induced seizures [35,36]. The WHO adverse drug reaction database from 1968 to 2006 showed amoxapine to be the second most reported cyclic antidepressant drug with seizures as an adverse event (8.7%) [37]. The database is based on spontaneous reporting and not on total use and might be misleading. Amoxapine should be avoided in patients with epilepsy. 2.3.3. Maprotiline Seizures associated with maprotiline treatment have been described in various case reports from the 1980s [38–40] even within usual dosage ranges. Whereas an early analysis of 98 cases of patients with depression without epilepsy with maprotiline-induced seizures did not show a clear relation to rapid dosage escalation or high serum concentrations, a dose reduction seemed to have positive effect [41]. A retrospective study among patients with depression showed a seizure risk of 15.6% in a dose range from 75 mg to 300 mg [42]. Even within the therapeutic range, the seizure risk seems to be dose-related [43]. The drug has a high (about 15%) risk for overdose-induced seizures [36,44]. The WHO adverse drug reaction database from 1968 to 2006 showed maprotiline to be the most reported drug with seizures as an adverse event (14.4%) [37]. Maprotiline should, therefore, be avoided in patients with epilepsy. 2.3.4. Bupropion Bupropion is used as an antidepressant and increasingly used in the treatment for smoking cessation. Initially, it was marketed as an immediate release, but later both sustained release and extended release formulations were approved. After its introduction in 1985, a significant incidence of seizures at the originally recommended dosages (400–600 mg) led to withdrawal of the drug from the market a year later. As the risk of seizures was found to be dose-dependent, bupropion was reintroduced in 1989 with a maximum recommended dose of 450 mg/day [45]. As expected, the drug has a high (N10%) risk for overdose-induced seizures [18]. In a review of FDA phase II and III studies for antidepressants, immediate release bupropion had an increased seizure risk (0.6%) comparable to clomipramine (0.7%), whereas the seizure risk for bupropion sustained release (0.1%) was within the normal range for other antidepressants [23]. The WHO adverse drug reaction database from 1968 to 2006 showed bupropion to be the third most reported drug with seizures as an adverse event (9.48%) [37], but this would include reports from 1985 when high dosages with immediate release bupropion were used. Bupropion increases the risk of seizures in a dose-related manner and should, therefore, be used with caution, in a low to moderate dosage and in a sustained/extended release formulation to avoid high peak serum concentrations. 3. Clinical implications Treatment of epilepsy and comorbid disorders requires a rational pharmacological approach regarding proper choice of drugs, susceptibility for drug interactions, tolerability, and optimal efficacy to avoid
Please cite this article as: Johannessen Landmark C, et al, Proconvulsant effects of antidepressants — What is the current evidence? Epilepsy Behav (2016), http://dx.doi.org/10.1016/j.yebeh.2016.01.029
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seizures. Excessive intake or overdose of antidepressants in general might cause seizures [18]. Interindividual factors that contribute to pharmacokinetic variability, pharmacokinetic or -dynamic drug interactions, or pharmacogenetic variability in metabolism may also cause supratherapeutic serum concentrations. Based on the assumption that most proconvulsant effects of antidepressants are concentrationrelated, this may be avoided in the individual patient. Individualization of drug therapy is an important concern, and it may be described as the tailoring of drug selection and dosing to the patient to optimize the efficacy and minimize toxicity [46,47]. In a clinical setting, patients with no prior diagnosis of epilepsy may experience seizures following the use of antidepressants. A large UK cohort including more than 200,000 patients aged 20–64 years old showed that the risk of a seizure increased for patients using trazodone, lofepramine, venlafaxine, and combined antidepressant treatment. There was no increased risk with sertraline, escitalopram, and mirtazapine [48]. Overall, the study demonstrated that all drug classes had an increased risk at all doses with TCAs and high doses of SSRIs. However, those patients who had a prior diagnosis of epilepsy (1.4%) were excluded in this study [48]. A similar study was performed in elderly people aged 65 years and above and showed a 2-fold risk of seizures in the elderly using all classes of antidepressants [49]. These studies do not point to mechanisms, only statistical risks in patients in general. The primary focus of the present review is, however, patients with epilepsy and depression. Situations where proconvulsant effects may be enhanced will be highlighted below. 3.1. Drug interactions Most antidepressants as well as AEDs are metabolized through the cytochrome P450 (CYP) system. Pharmacokinetic interactions, e.g., in combination with enzyme inhibitors of CYP2D6, as bupropion, or the AED stiripentol, may cause an increase in the serum concentration of antidepressants in such a way that proconvulsant effects arise [50]. Other antidepressants that may be used concomitantly and act as inhibitors of CYP2D6 include e.g., fluoxetine, sertraline, paroxetine, citalopram, and escitalopram (for review, see Mula, [51]). Even though valproic acid is a commonly used AED that is regarded as a potent enzyme inhibitor, it has not been demonstrated to inhibit CYP2D6 [52–54]. 3.2. Pharmacogenetic variability The main focus for pharmacogenetic variability of antidepressants is related to their route of metabolism where genetic differences exist. Most antidepressants undergo extensive metabolism, the main routes being through CYPs. There are various CYP isoenzymes, each of which is a specific gene product with characteristic substrate specificity [55]. Clinically important CYPs involve certain isoforms that appear to have therapeutic relevance for antidepressants, including CYP2C9/10, CYP2C19, and CYP2D6 [46]. Poor metabolizers of these enzymes resulting in a slow rate of metabolism will achieve high serum concentrations at therapeutic doses that might lead to toxicity or seizures with, for instance, clomipramine, amoxapine, and maprotiline. The proportion of homozygote poor metabolizers varies between various ethnic groups. 3.3. Implementation of therapeutic drug monitoring Therapeutic drug monitoring (TDM) may be a valuable tool for optimal drug therapy with AEDs or antidepressants for the individual patient. Pharmacokinetic variability among patients and within the same patient over time may be taken into account, including changes caused by increased age or comedication [55–58]. This may contribute to achieve a safer and more effective treatment, aiming at the lowest effective dose and serum concentration. Reasons for the implementation of TDM in clinical practice include aspects of compliance, pharmacokinetic
and pharmacogenetic variability as described above, and close monitoring of special patient populations, such as children, pregnant women, or the elderly [57]. For the actual drugs considered in this review, the elderly possibly represent the most vulnerable group of patients. They often have higher serum concentrations than younger adults because of changes in physiology and pharmacokinetics, such as decreased renal function and capacity for elimination of drugs through the liver [57]. In many situations, it is difficult to adjust the dosage on clinical grounds alone. The correct interpretation of TDM relies on standardization of blood sampling time, analytical procedures, and clinical judgment of the results [59,60]. The concept of an “individual therapeutic concentration” is defined as a concentration that produces the optimal response in the individual patient [56,59]. The goal is to focus upon drug safety and find the optimal balance between efficacy and tolerability in the individual patient [61]. Thus, too high serum concentrations may be associated with proconvulsant effects of certain antidepressants and should be avoided. 4. Conclusions Current evidence demonstrates that most antidepressants are regarded as safe and may be used in patients with epilepsy. New antidepressants such as SSRIs and SNRIs are first-line treatment options. The risk of seizures is regarded as small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy. Based on the evidence documented through the last decades, four of the older drugs should be avoided or used with caution — amoxapine, bupropion, clomipramine, and maprotiline. Bupropion is the drug that prescribers should pay specific attention to because of its increasing use in smoking cessation today, and if necessary, it should be used in an extended or sustained release formulation to avoid high peak serum concentrations. For an optimal drug treatment and avoidance of seizures, careful considerations of individual variability such as age and physiological state, potential for pharmacokinetic drug interactions and pharmacogenetic variability, and implementation of TDM contribute to improved safety of therapy. The lowest possible effective serum concentrations can, thus, be achieved, and the risk of seizures minimized, as an important concern regarding patient safety. Disclosure The authors have no conflicts of interest or any financial disclosures, sponsors or grants regarding this manuscript. The results have not previously been presented. References [1] Gaitaziz A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004;110(4):207–20. [2] Tellez-Zenteno JF, Patten SB, Jetté N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 2007;48(12):2236–44. [3] Fuller-Thomson E, Brennenstuhl S. The association between depression and epilepsy in a nationally representative sample. Epilepsia 2009;50(5):1051–8. [4] Karouni M, Arulthas S, Larsson PG, Rytter E, Johannessen Si, Landmark CJ. Psychiatric comorbidity in patients with epilepsy: a population-based study. Eur J Clin Pharmacol 2010;66(11):1151–60. [5] Kanner AM, Schachter SC, Barry JJ, Hersdorffer DC, Mula M, Trimble M, et al. Depression and epilepsy, pain and psychogenic non-epileptic seizures: clinical and therapeutic perspectives. Epilepsy Behav 2012;24(2):169–81. [6] Johannessen Landmark C. Relations between mechanisms of action and clinical efficacy of antiepileptic drugs in non-epilepsy conditions. CNS Drugs 2008;22:27–47. [7] Johannessen Landmark C, Larsson PG, Rytter E, Johannessen SI. Antiepileptic drugs in epilepsy and other disorders: a population-based study of prescriptions. Epilepsy Res 2009;87:31–9. [8] Perucca P, Mula M. Antiepileptic drug effects on mood and behaviour: molecular targets. Epilepsy Behav 2013;26(3):440–9. [9] Mula M, Monaco F, Trimble MR. Use of psychotropic drugs in patients with epilepsy: interactions and seizure risk. Expert Rev Neurother 2004;4(6):953–64.
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[35] White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by antidepressant type. J Med Toxicol 2008;4(4):238–50. [36] Litovitz TL, Troutman WG. Amoxapine overdose. Seizures and fatalities. JAMA 1983; 250(8):1069–71. [37] Kumlien E, Lundberg PO. Seizure risk associated with neuroactive drugs: data from the WHO adverse reactions database. Seizure 2010;19(2):69–73. [38] Hoffman BF, Wachsmuth R. Maptrotiline and seizures. J Clin Psychiatry 1982;43: 117–8. [39] Molnar G. Seizures associated with high maprotiline serum concentrations. Can J Psychiatry 1983;28:555–6. [40] Atri PB, Julius DA. Maprotiline hydrochloride associated with a clinical state of catatonic stupor and epileptic encephalogram. J Clin Psychopharmacol 1984;4:207–9. [41] Dessain EC, Schatzberg AF, Woods BT, Cole JO. Maprotiline treatment in depression. A perspective on seizures. Arch Gen Psychiatry 1986;43(1):86–90. [42] Jabbari B, Bryan GE, Marsh EE, Gunderson CH. Incidence of seizures with tricyclic and tetracyclic antidepressants. Arch Neurol 1985;42(5):480–1. [43] Skowron DM, Stimmel GL. Antidepressants and the risk of seizures. Pharmacotherapy 1992;12(1):18–22. [44] Wedin GP, Oderda GM, Klein-Schwartz W, Gorman RL. Relative toxicity of cyclic antidepressants. Ann Emerg Med 1986;15(7):797–804. [45] Davidson J. Seizures and bupropion: a review. J Clin Psychiatry 1989;50(7):256–61. [46] Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med 2006;57:119–37. [47] Lesko LJ, Schmidt S. Individualization of drug therapy: history, present state and opportunities for the future. Clin Pharmacol Ther 2012;92(4):458–66. [48] Hill T, Coupland C, Morriss R, Arthur A, Moore M, Hippisley-Cox J. Antidepressant use and risk of epilepsy and seizures in people aged 20 to 64 years: cohort study using a primary care database. BMC Psychiatry 2015;15:315. [49] Coupland C, Dhiman P, Morriss R, Arthus A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011;2:343 [d4551]. [50] Johannessen Landmark C, Patsalos PN. Methodologies used to identify and characterize interactions among antiepileptic drugs. Expert Rev Clin Pharmacol 2012; 5(3):281–92. [51] Mula M. Anticonvulsants–antidepressants pharmacokinetic interactions: the role of the CYP P450 system in psychopharmacology. Curr Drug Metab 2008;9(8):730–7. [52] Johannessen SI, Johannessen Landmark C. Antiepileptic drug interactions — basic principles and clinical implications. Curr Neuropharmacol 2010;8:254–67. [53] Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second and third generation antiepileptic drugs. Expert Rev Neurother 2010;10(1):119–40. [54] Johannessen Landmark C, Fossmark H, Larsson PG, Rytter E, Johannessen SI. Antiepileptic drug use in epilepsy — a population-based study. Epilepsy Res 2011;95:51–9. [55] The human cytochrome P450 (CYP) allele nomenclature database. Available at: http://www.cypalleles.ki.se/. [56] Bengtsson F. Therapeutic drug monitoring of psychotropic drugs. TDM “nouveau”. Ther Drug Monit 2004;26(2):145–51. [57] Johannessen Landmark C, Johannessen SI, Tomson T. Host factors affecting antiepileptic drug delivery — pharmacokinetic variability. Adv Drug Deliv Rev 2012;64: 896–910. [58] Waade RB, Molden E, Refsum H, Hermann M. Serum concentrations of antidepressants in the elderly. Ther Drug Monit 2012;34(1):25–30. [59] Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, et al. Antiepileptic drugs — best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49(7):1239–76. [60] Johannessen SI, Johannessen Landmark C. Value of therapeutic drug montoring in epilepsy. Expert Rev Neurother 2008;8(6):929–39. [61] Johannessen Landmark C, Johannessen SI. Drug safety aspects of antiepileptic drugs — focus on pharmacovigilance. Pharmacoepidemiol Drug Saf 2012;21(1): 11–20.
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Review
Proconvulsant effects of antidepressants — What is the current evidence? Cecilie Johannessen Landmark a,b,c,⁎, Oliver Henning b, Svein I. Johannessen b,c a b c
Dept. of Life Sciences and Health, Programme for Pharmacy, Faculty of Health Science, Oslo and Akershus University College of Applied Sciences, Oslo, Norway The National Center for Epilepsy, Sandvika, Oslo University Hospital, Oslo, Norway Department of Pharmacology, Oslo University Hospital, Oslo, Norway
a r t i c l e
i n f o
Article history: Revised 23 January 2016 Accepted 25 January 2016 Available online xxxx Keywords: Antidepressant drugs Proconvulsant Seizures Drug safety
a b s t r a c t Antidepressant drugs may have proconvulsant effects. Psychiatric comorbidity in epilepsy is common. Prescribers might be reluctant to initiate treatment with antidepressants in fear of seizure aggravation. The purpose of this review was to focus upon the current evidence for proconvulsant effects of antidepressants and possible clinical implications. Most antidepressants are regarded as safe and may be used in patients with epilepsy, such as the newer serotonin and/or noradrenaline reuptake inhibitors. Four older drugs should, however, be avoided or used with caution; amoxapine, bupropion, clomipramine and maprotiline. Proconvulsant effects are concentration-related. Optimization of drug treatment includes considerations of pharmacokinetic variability to avoid high serum concentrations of the most proconvulsant antidepressants. The risk of seizures is regarded as small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Antidepressants drugs have been used to treat symptoms of depression since they were introduced in the late 1950s. They consist of a broad range of drugs, all affecting the neurochemical balance of monoamine neurotransmitters in the central nervous system. Some antidepressants have been demonstrated to have proconvulsant effects. In the present review, the main focus will be on patients with epilepsy, since they are most vulnerable to have seizures because of a lower seizure threshold than the population as a whole. Seizures caused by excessive intake of antidepressants or overdose will, however, be briefly described in general. A prevalence rate of depression in epilepsy between 6 and 30% has been shown with various methods [1–5]. Patients with epilepsy and comorbid psychiatric disorders form a large group. Antiepileptic drugs have various beneficial pharmacological effects in psychiatric disorders and are increasingly used in such indications [6–8]. Extensive polypharmacy might lead to interactions and adverse effects [4,9]. Studies have shown that psychiatric disorders in these patients may be underdiagnosed and undertreated [10,11]. A recent survey showed that the main barrier in treating depression in patients with epilepsy is the fear of an increased seizure frequency, according to 52% of primary care physicians, and even 10% of neurologists [12]. Updated knowledge of which antidepressants may have proconvulsant effects and, thus, should be avoided is, therefore, of utmost importance.
⁎ Corresponding author at: Dept. of Life Sciences and Health, Programme for Pharmacy, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Pilestredet 50, N-0167 Oslo, Norway. Tel.: +47 22452360; fax: +47 22452335. E-mail address: [email protected] (C. Johannessen Landmark).
The purpose of the present review was to focus upon the current evidence of possible proconvulsant effects of antidepressants and their clinical implications, in order to help prescribers decide which antidepressants should be avoided in patients with epilepsy. 1.1. Description of antidepressants Antidepressant drugs are defined according to the classification of drugs based upon the Anatomical Therapeutic Chemical classification (ATC)-codes where antiepileptic drugs (AEDs) are defined as N06A [13]. Classification of antidepressants is summarized in Table 1. The main categories include the newer selective serotonin reuptake inhibitors (SSRIs), the older nonselective monoamine reuptake inhibitors or tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, selective or nonselective for MAOA, and other antidepressants. They also include the newer selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, duloxetine, reboxetine). Their possible propensities to cause proconvulsant effects will be described. 1.2. Search criteria and literature review The present review is based upon recently published articles identified by searches in PubMed and Google Scholar, in addition to the authors' files. Selected publications of interest were included (1982–2015) with emphasis on the last five years. The search period was to January 2016. Peer-reviewed articles or abstracts on the topic in recognized international journals in English were included, whereas non-English articles were disregarded. Both preclinical and clinical and acute and chronic studies were regarded as relevant, as well as the use of various animal models. Review articles giving a broad and updated overview
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Table 1 Classification of antidepressants and their propensity to cause seizures. Antidepressant drug classes
Drug examples
Drugs with propensity to cause seizures and metabolic pathway
Nonselective monoamine reuptake inhibitors (TCA)
Amitriptyline, doxepin, nortriptyline, trimipramine
Selective serotonin reuptake inhibitors (SSRI)
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline Venlafaxine, reboxetine, duloxetine
Clomipramine (CYP1A2, 3A4, 2D6) None
Selective noradrenaline or noradrenaline/serotonin reuptake inhibitors (SNRI) Monoamine oxidase inhibitors (MAO), nonselective Monoamine oxidase A inhibitors (MAOA) Other antidepressants
Moclobemide Mianserin, mirtazapine
None Maprotiline (CYP2D6), amoxapine (CYP2D6) None Bupropion (CYP2B6), inhibitor of CYP2D6
The classification of antidepressants is based on the ATC classification system [13].
regarding possible proconvulsant effects of antidepressants were also included. General reviews with a scope besides proconvulsant effects were disregarded. During the searches, the key words antidepressants (specific searches for amoxapine, bupropion, clomipramine, maprotiline, mianserin), anticonvulsant, antiepileptic drugs, clinical study, dose, drug safety, interactions, mice, overdose, preclinical study, proconvulsant, SNRI, SSRI, rat, therapeutic drug monitoring, tricyclic antidepressant, and zebrafish were used, and the various key words were combined. 2. Proconvulsant effects of antidepressants
GABAergic and excitatory glutamatergic neurotransmission with increase in glutamatergic activation and, thus, excessive calcium influx, initiating intracellular processes. The underlying mechanisms are not clear [14]. In a recent review, the role of serotonin in the control of neuronal excitability, epileptogenesis, and seizure propagation is emphasized, and various effects are observed through modulation of different subtypes of 5-HT receptors throughout the brain [15]. Noradrenergic and serotonergic effects of antidepressants seem to be anticonvulsant in therapeutic doses, whereas supratherapeutic doses or serum concentrations may activate other neurochemical pathways that may culminate in seizures [16–18].
2.1. Neurochemical background 2.2. Preclinical evidence of specific drugs The monoamines are the main neurotransmitters that are affected by antidepressants. It is well known that it takes several weeks to observe clinical effects of these drugs, pointing to a long-term change in establishing a neurochemical balance within these neuronal networks. The main targets for pharmacological action of antidepressants vs AEDs in the synapses are shown in Fig. 1. Antidepressants may disturb the neuronal balance and control of excitability, leading to seizures. Seizures may occur as a consequence of a misbalance between inhibitory
When reviewing the literature, four antidepressants, in particular, appear to have most pronounced proconvulsant effects, namely the tricyclic antidepressant clomipramine, the unselective MAO-inhibitors amoxapine and maprotiline, and the atypical antidepressant bupropion, the latter being a noradrenaline and dopamine reuptake inhibitor (Table 1). For all other antidepressants, the seizure risk is regarded as low.
Fig. 1. Mechanisms of action of antidepressants vs antiepileptic drugs in the synapses.
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It is difficult to extrapolate results from in vitro data to clinical practice, as variability in methodology and complex effects might be impossible to predict [19]. In addition, the experimental evidence for the proconvulsant effects of several antidepressants, including clomipramine, amoxapine, and bupropion, is based upon early studies in animals where relatively high doses were administered. For example, in the study by Peterson et al. [20], clomipramine was administered at doses of 20–40 mg/kg, amoxapine at 20–40 mg/kg, or desipramine at 10– 20 mg/kg, which all are far above therapeutic doses. Acute vs chronic effects of the seizure threshold may vary, and chronic effects may have a more pronounced effect than acute effects. Chronic administration of clomipramine, amoxapine, or desimipramine in rats for twenty days demonstrated an increased susceptibility for the animals to have seizures than with mianserin, whereas no effects were seen after acute administration of one dose [20]. This was explained based on the prolonged effects of these antidepressants on noradrenergic balance that would affect excitability. It has been suggested that the proconvulsant liability of antidepressants may be both concentrationand model-dependent, as demonstrated in a study with seizures in mice and zebrafish with drugs as reboxetine and bupropion [21]. The mouse model with pilocarpine-induced seizures was more sensitive to lowering of the seizure threshold than pentylenetetrazoleinduced seizures in both mice and zebrafish [21]. In another recent study, electroencephalographical (EEG) measurement in the fentanyl/ etomidate-anesthetized beagle (FEAB) model was implemented in order to detect burst suppression and/or seizure development caused by proconvulsant compounds as bupropion and showed to be suitable in pharmacological studies [22]. 2.3. Clinical evidence of specific drugs Documentation from randomized controlled trials regarding the seizure frequency when treating patients with epilepsy with antidepressants is sparse. As described in the section of preclinical evidence, for most antidepressants, the risk of seizures is small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy. The newer classes of antidepressants, SSRIs and SNRIs, are safe for people with epilepsy, and they seem to obtain therapeutic responses independently of seizure frequency. These drugs appear to have a potential for anticonvulsant effects rather than proconvulsant effects [23–25]. Most information comes from the nonepileptic population from premarketing trials where epilepsy often is an exclusion criterion or from postmarketing analyses where the conditions and data are much more variable. In the nonepileptic population, an increased seizure risk has, among others, been associated with high serum concentrations, which can be due to slow metabolism and a rapid dose titration [14,26–29]. This is supported by the fact that some antidepressants may have anticonvulsant properties when used in low dosages while they are proconvulsant in higher dosages [19]. Clomipramine, maprotiline, amoxapine, and bupropion are especially regarded to have a high risk to increase seizures when used in patients with epilepsy [28], with increasing risk in intentional or accidental overdose [18]. For mianserin, however, no further clinical evidence was found. The available data in this context must be interpreted in relation with the fact that there is a bidirectional relationship between depression and epilepsy. People with epilepsy are at increased risk for depression. On the other hand, people with psychiatric disorders, including depression, have a two- to sevenfold risk of developing seizures/epilepsy at some stage [30,31]. Therefore, the occurrence of seizures in a patient with depression may be an expression of the natural course of the disease, rather than an adverse effect of antidepressant therapy [32]. 2.3.1. Clomipramine This drug is no longer as clinically relevant as an antidepressant since the majority of use of antidepressants consists of newer and
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more selective drugs (SSRIs). A possible proconvulsant effect of clomipramine has, however, only been demonstrated in supratherapeutic doses in animals (20–40 mg/kg) [20]. Therapeutic doses are usually in the order of 50 and up to 150 mg/day. But clomipramine is still used to some degree, mainly for the indication of obsessive–compulsive disorder (OCD). In a review from the US Food and Drug Administration (FDA) phase II and III studies for psychopharmacological drugs with regard to seizures, Alper et al. [23] found clomipramine used for OCD to have the highest risk (0.7%) among the included drugs. The drug has an intermediate (5%–10%) risk for overdose-induced seizures [18]. If possible, it should be avoided in patients with epilepsy. 2.3.2. Amoxapine Various case reports describe seizures associated with amoxapine treatment also within usual dosage ranges, mainly from the 1980s [33, 34]. The drug has a high (about 30%) risk for overdose-induced seizures [35,36]. The WHO adverse drug reaction database from 1968 to 2006 showed amoxapine to be the second most reported cyclic antidepressant drug with seizures as an adverse event (8.7%) [37]. The database is based on spontaneous reporting and not on total use and might be misleading. Amoxapine should be avoided in patients with epilepsy. 2.3.3. Maprotiline Seizures associated with maprotiline treatment have been described in various case reports from the 1980s [38–40] even within usual dosage ranges. Whereas an early analysis of 98 cases of patients with depression without epilepsy with maprotiline-induced seizures did not show a clear relation to rapid dosage escalation or high serum concentrations, a dose reduction seemed to have positive effect [41]. A retrospective study among patients with depression showed a seizure risk of 15.6% in a dose range from 75 mg to 300 mg [42]. Even within the therapeutic range, the seizure risk seems to be dose-related [43]. The drug has a high (about 15%) risk for overdose-induced seizures [36,44]. The WHO adverse drug reaction database from 1968 to 2006 showed maprotiline to be the most reported drug with seizures as an adverse event (14.4%) [37]. Maprotiline should, therefore, be avoided in patients with epilepsy. 2.3.4. Bupropion Bupropion is used as an antidepressant and increasingly used in the treatment for smoking cessation. Initially, it was marketed as an immediate release, but later both sustained release and extended release formulations were approved. After its introduction in 1985, a significant incidence of seizures at the originally recommended dosages (400–600 mg) led to withdrawal of the drug from the market a year later. As the risk of seizures was found to be dose-dependent, bupropion was reintroduced in 1989 with a maximum recommended dose of 450 mg/day [45]. As expected, the drug has a high (N10%) risk for overdose-induced seizures [18]. In a review of FDA phase II and III studies for antidepressants, immediate release bupropion had an increased seizure risk (0.6%) comparable to clomipramine (0.7%), whereas the seizure risk for bupropion sustained release (0.1%) was within the normal range for other antidepressants [23]. The WHO adverse drug reaction database from 1968 to 2006 showed bupropion to be the third most reported drug with seizures as an adverse event (9.48%) [37], but this would include reports from 1985 when high dosages with immediate release bupropion were used. Bupropion increases the risk of seizures in a dose-related manner and should, therefore, be used with caution, in a low to moderate dosage and in a sustained/extended release formulation to avoid high peak serum concentrations. 3. Clinical implications Treatment of epilepsy and comorbid disorders requires a rational pharmacological approach regarding proper choice of drugs, susceptibility for drug interactions, tolerability, and optimal efficacy to avoid
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seizures. Excessive intake or overdose of antidepressants in general might cause seizures [18]. Interindividual factors that contribute to pharmacokinetic variability, pharmacokinetic or -dynamic drug interactions, or pharmacogenetic variability in metabolism may also cause supratherapeutic serum concentrations. Based on the assumption that most proconvulsant effects of antidepressants are concentrationrelated, this may be avoided in the individual patient. Individualization of drug therapy is an important concern, and it may be described as the tailoring of drug selection and dosing to the patient to optimize the efficacy and minimize toxicity [46,47]. In a clinical setting, patients with no prior diagnosis of epilepsy may experience seizures following the use of antidepressants. A large UK cohort including more than 200,000 patients aged 20–64 years old showed that the risk of a seizure increased for patients using trazodone, lofepramine, venlafaxine, and combined antidepressant treatment. There was no increased risk with sertraline, escitalopram, and mirtazapine [48]. Overall, the study demonstrated that all drug classes had an increased risk at all doses with TCAs and high doses of SSRIs. However, those patients who had a prior diagnosis of epilepsy (1.4%) were excluded in this study [48]. A similar study was performed in elderly people aged 65 years and above and showed a 2-fold risk of seizures in the elderly using all classes of antidepressants [49]. These studies do not point to mechanisms, only statistical risks in patients in general. The primary focus of the present review is, however, patients with epilepsy and depression. Situations where proconvulsant effects may be enhanced will be highlighted below. 3.1. Drug interactions Most antidepressants as well as AEDs are metabolized through the cytochrome P450 (CYP) system. Pharmacokinetic interactions, e.g., in combination with enzyme inhibitors of CYP2D6, as bupropion, or the AED stiripentol, may cause an increase in the serum concentration of antidepressants in such a way that proconvulsant effects arise [50]. Other antidepressants that may be used concomitantly and act as inhibitors of CYP2D6 include e.g., fluoxetine, sertraline, paroxetine, citalopram, and escitalopram (for review, see Mula, [51]). Even though valproic acid is a commonly used AED that is regarded as a potent enzyme inhibitor, it has not been demonstrated to inhibit CYP2D6 [52–54]. 3.2. Pharmacogenetic variability The main focus for pharmacogenetic variability of antidepressants is related to their route of metabolism where genetic differences exist. Most antidepressants undergo extensive metabolism, the main routes being through CYPs. There are various CYP isoenzymes, each of which is a specific gene product with characteristic substrate specificity [55]. Clinically important CYPs involve certain isoforms that appear to have therapeutic relevance for antidepressants, including CYP2C9/10, CYP2C19, and CYP2D6 [46]. Poor metabolizers of these enzymes resulting in a slow rate of metabolism will achieve high serum concentrations at therapeutic doses that might lead to toxicity or seizures with, for instance, clomipramine, amoxapine, and maprotiline. The proportion of homozygote poor metabolizers varies between various ethnic groups. 3.3. Implementation of therapeutic drug monitoring Therapeutic drug monitoring (TDM) may be a valuable tool for optimal drug therapy with AEDs or antidepressants for the individual patient. Pharmacokinetic variability among patients and within the same patient over time may be taken into account, including changes caused by increased age or comedication [55–58]. This may contribute to achieve a safer and more effective treatment, aiming at the lowest effective dose and serum concentration. Reasons for the implementation of TDM in clinical practice include aspects of compliance, pharmacokinetic
and pharmacogenetic variability as described above, and close monitoring of special patient populations, such as children, pregnant women, or the elderly [57]. For the actual drugs considered in this review, the elderly possibly represent the most vulnerable group of patients. They often have higher serum concentrations than younger adults because of changes in physiology and pharmacokinetics, such as decreased renal function and capacity for elimination of drugs through the liver [57]. In many situations, it is difficult to adjust the dosage on clinical grounds alone. The correct interpretation of TDM relies on standardization of blood sampling time, analytical procedures, and clinical judgment of the results [59,60]. The concept of an “individual therapeutic concentration” is defined as a concentration that produces the optimal response in the individual patient [56,59]. The goal is to focus upon drug safety and find the optimal balance between efficacy and tolerability in the individual patient [61]. Thus, too high serum concentrations may be associated with proconvulsant effects of certain antidepressants and should be avoided. 4. Conclusions Current evidence demonstrates that most antidepressants are regarded as safe and may be used in patients with epilepsy. New antidepressants such as SSRIs and SNRIs are first-line treatment options. The risk of seizures is regarded as small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy. Based on the evidence documented through the last decades, four of the older drugs should be avoided or used with caution — amoxapine, bupropion, clomipramine, and maprotiline. Bupropion is the drug that prescribers should pay specific attention to because of its increasing use in smoking cessation today, and if necessary, it should be used in an extended or sustained release formulation to avoid high peak serum concentrations. For an optimal drug treatment and avoidance of seizures, careful considerations of individual variability such as age and physiological state, potential for pharmacokinetic drug interactions and pharmacogenetic variability, and implementation of TDM contribute to improved safety of therapy. The lowest possible effective serum concentrations can, thus, be achieved, and the risk of seizures minimized, as an important concern regarding patient safety. Disclosure The authors have no conflicts of interest or any financial disclosures, sponsors or grants regarding this manuscript. The results have not previously been presented. References [1] Gaitaziz A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand 2004;110(4):207–20. [2] Tellez-Zenteno JF, Patten SB, Jetté N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 2007;48(12):2236–44. [3] Fuller-Thomson E, Brennenstuhl S. The association between depression and epilepsy in a nationally representative sample. Epilepsia 2009;50(5):1051–8. [4] Karouni M, Arulthas S, Larsson PG, Rytter E, Johannessen Si, Landmark CJ. Psychiatric comorbidity in patients with epilepsy: a population-based study. Eur J Clin Pharmacol 2010;66(11):1151–60. [5] Kanner AM, Schachter SC, Barry JJ, Hersdorffer DC, Mula M, Trimble M, et al. Depression and epilepsy, pain and psychogenic non-epileptic seizures: clinical and therapeutic perspectives. Epilepsy Behav 2012;24(2):169–81. [6] Johannessen Landmark C. Relations between mechanisms of action and clinical efficacy of antiepileptic drugs in non-epilepsy conditions. CNS Drugs 2008;22:27–47. [7] Johannessen Landmark C, Larsson PG, Rytter E, Johannessen SI. Antiepileptic drugs in epilepsy and other disorders: a population-based study of prescriptions. Epilepsy Res 2009;87:31–9. [8] Perucca P, Mula M. Antiepileptic drug effects on mood and behaviour: molecular targets. Epilepsy Behav 2013;26(3):440–9. [9] Mula M, Monaco F, Trimble MR. Use of psychotropic drugs in patients with epilepsy: interactions and seizure risk. Expert Rev Neurother 2004;4(6):953–64.
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