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Increased risk of suicidality on perampanel (Fycompa®)?
Epilepsy & Behavior 31 (2014) 71–72
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Letter to the Editor Increased risk of suicidality on perampanel (Fycompa®)? To the Editor In the long-stay department of the Bethel Epilepsy Center, 23 adult patients with highly therapy-resistant epilepsy were started on perampanel (PER) from its introduction to the market in 2012 until the end of August 2013. We have recently observed three cases of suicidality in patients on (PER). We, therefore, are concerned about the risk of psychiatric adverse effects of PER, particularly suicidal ideas or behavior, which might have been underestimated. Perampanel is an AED with a novel mechanism of action (antagonism at AMPA-type glutamate receptors), indicated for patients with treatment-resistant focal epilepsy. In the manufacturer's product leaflet on PER, suicidality is only referred to in terms of a potential general risk in the context of antiepileptic pharmacotherapy [1]. A possible substance-specific suicidality risk is not mentioned. Other psychiatric adverse effects mentioned in the product leaflet include aggression, anger, anxiety, and confusional state. In a more detailed information leaflet provided by Eisai, the manufacturer, all psychic effects documented in the 3 pivotal phase III studies [2–4] are listed. According to this, only 2 out of more than 1000 (0.2%) patients on PER reported on suicidal ideas as compared with 2 out of 442 (0.5%) patients on placebo. In the extension study [5] which included approximately 1200 patients, 6 cases of suicidal ideation were reported, 4 of them requiring hospitalization. According to the information leaflet, 3 of the cases were suicide attempts. Irritability (9.8%) was the most frequent treatment-emergent adverse event in the psychiatric field. The information sheet concludes that there is no increased risk of suicidality on PER. Our observations suggest that this conclusion may be premature. Case 1 is a 21-year-old woman with highly therapy-resistant focal epilepsy of unknown origin. She had suffered from simple and complex partial as well as generalized tonic–clonic seizures since the age of seven. Nearly all available AEDs had already been tried unsuccessfully (therapy resistance degree 3; [6]). Epilepsy surgery was not an option. Her cognitive abilities were slightly reduced. Perampanel (2 mg/day) was started in March 2013. Dosage increases occurred somewhat slower than recommended by the manufacturer. In the beginning of June 2013, at a dosage of 8 mg/day (comedication lamotrigine and valproic acid), she stated that she tolerated the new drug very well. A month later, she complained about weight increase and some dizziness and blurred vision, but soon it turned out that she was unusually sensitive, irritable, and would get upset over any minor adversity. Three days later, she explained that she had been having suicidal ideas for 3 to 4 weeks (she would take a knife and prick it into her heart). Perampanel was immediately discontinued, and she recovered after a few days. Case 2 (22 years old, female) resembles case 1 in a number of aspects: focal epilepsy of unknown origin since the age of seven; partial 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.11.017
and secondary generalized seizures; therapy resistance degree 3; no surgical option; and slight cognitive deficits. As a difference, she had a history of suicidality (attempted suicide by taking an overdose of medication when she was on levetiracetam, seven years earlier). At a dosage of 4 mg/day PER (comedication oxcarbazepine and retigabine) she felt sometimes unwell and dizzy after taking the medication in the evening. Somewhat later, 8 weeks after starting PER, she reported that she was feeling thin-skinned, abnormally sensitive, and aggressive since approximately four weeks ago. She had been having suicidal ideas for some days. Bothered by minor conflicts in her sheltered workshop, she tried to stick a knife into her thigh. Her condition normalized within some days after PER was stopped. Case 3 is a 22-year-old man. His epilepsy and intellectual disability of moderate degree resulted from bilateral perisylvian polymicrogyria (Foix–Chavany–Marie syndrome). His tonic and tonic–hypermotor seizures had started when he was nine. He had therapy resistance degree 2 (history of five unsuccessful AED trials). At 100-mg/day PER, he experienced some nausea and dizziness after medication intake in the evening. Some weeks later, approximately 4 months after PER had been added to his prior medication of lamotrigine, it was reported that he had become suicidal. He had “bad thoughts”, and he repeatedly visualized a “film scene” in which he was standing on rails and was rolled over by a train. He was questioning his self-worth, and he reported feelings of angst and sadness. All these problems resolved shortly after PER was stopped. 1. Similarities and differences between the cases All three patients have difficult-to-treat focal epilepsy. All have cognitive impairments albeit of different degrees. The interval from the initiation of PER until the suicidal symptoms became manifest varied between 8 weeks and approximately 4 months. However, in all of the cases, it turned out that suicidal ideation was occurring but unrecognized for weeks (approximately 3 to 8 weeks) before it was reported by the patient or noticed by the staff. Perampanel dosages varied from 4 to 10 mg/day; the serum concentrations were not high (200 ng/ml in patient 1, 119 ng/ml in patient 2; not determined in case 3). The 3 patients had different comedications with unremarkable serum concentrations. Seizure frequency or intensity did not improve in any patient. All of the patients also had somatic adverse effects (dizziness in all cases, blurred vision, weight increase, feeling unwell, nausea). Psychopathologically, cases 1 and 2 were similar. Both patients were not actually depressed. Their suicidal impulses were rather based on highly increased sensitivity and irritability. Case 3, on the contrary, showed clear clinical signs of depression. One might question, however, whether his imagination of being killed by a riding train can be considered as suicidal or rather as an expression of fear of death in the context of his depression. However, fear of dying and the wish to die can be closely related in depressive patients, and they may be even more difficult to distinguish in a mentally impaired person. In this latter patient, the actual symptoms can be conceived as congruent with some aspects of his personality (he liked to watch horror films).
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Letter to the Editor
The history of a suicide attempt when on LEV was probably a risk factor in patient 2. The fact that the suicidal impulses in the first two cases were rather based on irritability than on depression may point to a link to an (dosedependent) increase in aggression which was (unlike suicidality) indicated in the package information.
Acknowledgment M. Bocchicchio and O. Rahn-Wiebe have provided valuable information on two of the patients.
References 2. Conclusions Three observed cases of suicidality out of the 23 patients treated with PER in our organization differs strikingly from the two suicidal cases documented among 1038 patients in the pivotal phase III studies and also from the six cases in the extension study. Therefore, the risk of suicidal ideas or behavior induced by PER may be higher than has been assumed up to now. One might hypothesize that the risk might be increased in a selected patient population (highly difficult-to-treat epilepsies, often combined with cognitive impairment) like ours. As a matter of fact, our observation should not be overinterpreted. As the number of patients treated with PER is relatively low, we cannot exclude that this cluster of cases of suicidality is only accidental. Nevertheless, increased vigilance is certainly justified. Particular concern arises from the fact that the emotional changes developed by the patients initially remained unnoticed by their surroundings. Only with a delay of weeks the suicidal ideas became apparent. We have now made it a habit interrogate every patient on PER not only in general terms about the occurrence of side effects but explicitly about possible emotional changes.
[1] Mula M, Kanner AM, Schmitz B, Schachter S. Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia 2013;54:199–203. [2] French J, Krauss G, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for refractory partial-onset seizures; randomised phase III study 304. Neurology 2012;79:589–96. [3] French J, Krauss G, Steinhoff B, Squillacote D, Yang H, Kumar D, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of a randomized global phase III study 305. Epilepsia 2013;54:117–25. [4] Krauss G, Serratosa J, Villanueva V, Endziniene M, Hong Z, French J, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408–15. [5] Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, et al. Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307. Epilepsia 2013;54:126–34. [6] Gomez-Alonso J, Gil-Nagel A. A graded system to categorize drug-resistant epilepsy. Epilepsia 2010;51:2360–1.
Bernd Huber Bethel Epilepsy Centre, Ebenezerweg 18, 33617 Bielefeld, Germany E-mail address: [email protected]. 5 November 2013
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Letter to the Editor Increased risk of suicidality on perampanel (Fycompa®)? To the Editor In the long-stay department of the Bethel Epilepsy Center, 23 adult patients with highly therapy-resistant epilepsy were started on perampanel (PER) from its introduction to the market in 2012 until the end of August 2013. We have recently observed three cases of suicidality in patients on (PER). We, therefore, are concerned about the risk of psychiatric adverse effects of PER, particularly suicidal ideas or behavior, which might have been underestimated. Perampanel is an AED with a novel mechanism of action (antagonism at AMPA-type glutamate receptors), indicated for patients with treatment-resistant focal epilepsy. In the manufacturer's product leaflet on PER, suicidality is only referred to in terms of a potential general risk in the context of antiepileptic pharmacotherapy [1]. A possible substance-specific suicidality risk is not mentioned. Other psychiatric adverse effects mentioned in the product leaflet include aggression, anger, anxiety, and confusional state. In a more detailed information leaflet provided by Eisai, the manufacturer, all psychic effects documented in the 3 pivotal phase III studies [2–4] are listed. According to this, only 2 out of more than 1000 (0.2%) patients on PER reported on suicidal ideas as compared with 2 out of 442 (0.5%) patients on placebo. In the extension study [5] which included approximately 1200 patients, 6 cases of suicidal ideation were reported, 4 of them requiring hospitalization. According to the information leaflet, 3 of the cases were suicide attempts. Irritability (9.8%) was the most frequent treatment-emergent adverse event in the psychiatric field. The information sheet concludes that there is no increased risk of suicidality on PER. Our observations suggest that this conclusion may be premature. Case 1 is a 21-year-old woman with highly therapy-resistant focal epilepsy of unknown origin. She had suffered from simple and complex partial as well as generalized tonic–clonic seizures since the age of seven. Nearly all available AEDs had already been tried unsuccessfully (therapy resistance degree 3; [6]). Epilepsy surgery was not an option. Her cognitive abilities were slightly reduced. Perampanel (2 mg/day) was started in March 2013. Dosage increases occurred somewhat slower than recommended by the manufacturer. In the beginning of June 2013, at a dosage of 8 mg/day (comedication lamotrigine and valproic acid), she stated that she tolerated the new drug very well. A month later, she complained about weight increase and some dizziness and blurred vision, but soon it turned out that she was unusually sensitive, irritable, and would get upset over any minor adversity. Three days later, she explained that she had been having suicidal ideas for 3 to 4 weeks (she would take a knife and prick it into her heart). Perampanel was immediately discontinued, and she recovered after a few days. Case 2 (22 years old, female) resembles case 1 in a number of aspects: focal epilepsy of unknown origin since the age of seven; partial 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.11.017
and secondary generalized seizures; therapy resistance degree 3; no surgical option; and slight cognitive deficits. As a difference, she had a history of suicidality (attempted suicide by taking an overdose of medication when she was on levetiracetam, seven years earlier). At a dosage of 4 mg/day PER (comedication oxcarbazepine and retigabine) she felt sometimes unwell and dizzy after taking the medication in the evening. Somewhat later, 8 weeks after starting PER, she reported that she was feeling thin-skinned, abnormally sensitive, and aggressive since approximately four weeks ago. She had been having suicidal ideas for some days. Bothered by minor conflicts in her sheltered workshop, she tried to stick a knife into her thigh. Her condition normalized within some days after PER was stopped. Case 3 is a 22-year-old man. His epilepsy and intellectual disability of moderate degree resulted from bilateral perisylvian polymicrogyria (Foix–Chavany–Marie syndrome). His tonic and tonic–hypermotor seizures had started when he was nine. He had therapy resistance degree 2 (history of five unsuccessful AED trials). At 100-mg/day PER, he experienced some nausea and dizziness after medication intake in the evening. Some weeks later, approximately 4 months after PER had been added to his prior medication of lamotrigine, it was reported that he had become suicidal. He had “bad thoughts”, and he repeatedly visualized a “film scene” in which he was standing on rails and was rolled over by a train. He was questioning his self-worth, and he reported feelings of angst and sadness. All these problems resolved shortly after PER was stopped. 1. Similarities and differences between the cases All three patients have difficult-to-treat focal epilepsy. All have cognitive impairments albeit of different degrees. The interval from the initiation of PER until the suicidal symptoms became manifest varied between 8 weeks and approximately 4 months. However, in all of the cases, it turned out that suicidal ideation was occurring but unrecognized for weeks (approximately 3 to 8 weeks) before it was reported by the patient or noticed by the staff. Perampanel dosages varied from 4 to 10 mg/day; the serum concentrations were not high (200 ng/ml in patient 1, 119 ng/ml in patient 2; not determined in case 3). The 3 patients had different comedications with unremarkable serum concentrations. Seizure frequency or intensity did not improve in any patient. All of the patients also had somatic adverse effects (dizziness in all cases, blurred vision, weight increase, feeling unwell, nausea). Psychopathologically, cases 1 and 2 were similar. Both patients were not actually depressed. Their suicidal impulses were rather based on highly increased sensitivity and irritability. Case 3, on the contrary, showed clear clinical signs of depression. One might question, however, whether his imagination of being killed by a riding train can be considered as suicidal or rather as an expression of fear of death in the context of his depression. However, fear of dying and the wish to die can be closely related in depressive patients, and they may be even more difficult to distinguish in a mentally impaired person. In this latter patient, the actual symptoms can be conceived as congruent with some aspects of his personality (he liked to watch horror films).
72
Letter to the Editor
The history of a suicide attempt when on LEV was probably a risk factor in patient 2. The fact that the suicidal impulses in the first two cases were rather based on irritability than on depression may point to a link to an (dosedependent) increase in aggression which was (unlike suicidality) indicated in the package information.
Acknowledgment M. Bocchicchio and O. Rahn-Wiebe have provided valuable information on two of the patients.
References 2. Conclusions Three observed cases of suicidality out of the 23 patients treated with PER in our organization differs strikingly from the two suicidal cases documented among 1038 patients in the pivotal phase III studies and also from the six cases in the extension study. Therefore, the risk of suicidal ideas or behavior induced by PER may be higher than has been assumed up to now. One might hypothesize that the risk might be increased in a selected patient population (highly difficult-to-treat epilepsies, often combined with cognitive impairment) like ours. As a matter of fact, our observation should not be overinterpreted. As the number of patients treated with PER is relatively low, we cannot exclude that this cluster of cases of suicidality is only accidental. Nevertheless, increased vigilance is certainly justified. Particular concern arises from the fact that the emotional changes developed by the patients initially remained unnoticed by their surroundings. Only with a delay of weeks the suicidal ideas became apparent. We have now made it a habit interrogate every patient on PER not only in general terms about the occurrence of side effects but explicitly about possible emotional changes.
[1] Mula M, Kanner AM, Schmitz B, Schachter S. Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia 2013;54:199–203. [2] French J, Krauss G, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for refractory partial-onset seizures; randomised phase III study 304. Neurology 2012;79:589–96. [3] French J, Krauss G, Steinhoff B, Squillacote D, Yang H, Kumar D, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of a randomized global phase III study 305. Epilepsia 2013;54:117–25. [4] Krauss G, Serratosa J, Villanueva V, Endziniene M, Hong Z, French J, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408–15. [5] Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Squillacote D, et al. Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307. Epilepsia 2013;54:126–34. [6] Gomez-Alonso J, Gil-Nagel A. A graded system to categorize drug-resistant epilepsy. Epilepsia 2010;51:2360–1.
Bernd Huber Bethel Epilepsy Centre, Ebenezerweg 18, 33617 Bielefeld, Germany E-mail address: [email protected]. 5 November 2013