Russian Journal of Child NeurologyRussian Journal of Child NeurologyРусский журнал детской неврологии2073-88032412-9178Publishing House ABV Press30810.17650/2073-8803-2019-14-3-37-58REVIEWS AND LECTURESОБЗОРЫ И ЛЕКЦИИSafety and tolerability of antiepileptic therapy: emphasis on the use of valproates (literature review)Актуальные вопросы безопасности и переносимости антиэпилептической терапии: акцент на применение препаратов вальпроевой кислоты (обзор литературы)PylaevaO. A.ПылаеваО. А.
Russian Federation

5 Nagornaya St., Troitsk, Moscow 108840, Russia; 9 Akad. Anokhina St., Moscow 119571, Russia

Россия, 108841 Москва, Троицк, ул. Нагорная, 5;Россия, 119579 Россия, Москва, ул. Акад. Анохина, 9

center@epileptologist.ruMukhinK. Yu.МухинК. Ю.
Russian Federation

5 Nagornaya St., Troitsk, Moscow 108840, Russia; 9 Akad. Anokhina St., Moscow 119571, Russia

Россия, 108841 Москва, Троицк, ул. Нагорная, 5;Россия, 119579 Россия, Москва, ул. Акад. Анохина, 9

St. Luka’s Institute of Child Neurology and EpilepsyООО «Институт детской неврологии и эпилепсии им. Свт. Луки»St. Luka’s Institute of Pediatric and Adult Neurology and EpilepsyООО «Институт детской и взрослой неврологии и эпилепсии им. Свт. Луки»St. Luka’s Institute of Child Neurology and EpilepsySt. Luka’s Institute of Pediatric and Adult Neurology and EpilepsyООО «Институт детской неврологии и эпилепсии им. Свт. Луки»ООО «Институт детской и взрослой неврологии и эпилепсии им. Свт. Луки»1507201914337601601202016012020Copyright ©; 2019, ABV-PressCopyright ©; 2019, АБВ-пресс2019ABV-PressАБВ-прессhttps://rjdn.abvpress.ru/jour/about/editorialPolicieshttps://rjdn.abvpress.ru/jour/article/view/308

Since epilepsy is a chronic disease of the nervous system that requires long-term therapy and regular intake of antiepileptic drugs, good tolerability of therapy is crucial for the quality of life of these patients. The main aim of antiepileptic treatment is the creation of a balance between the efficacy and tolerability of therapy. This literature review analyzes tolerability and safety of antiepileptic therapy. We paid particular attention to valproate, a drug that has been used for the treatment of epilepsy for more than 57 years. Valproate remains a basic drug with high efficacy and well-studied safety and tolerability. This review also covers the problems of epilepsy aggravation in response to some antiepileptic drugs, effects of antiepileptic drugs on cognitive functions, behavior, and mental sphere, as well as the issues of tolerability and safety of antiepileptic drugs in women of reproductive age.

C учетом того, что эпилепсия относится к хроническим заболеваниям нервной системы, требующим длительной многолетней терапии и регулярного ежедневного приема антиэпилептических препаратов, важную роль для качества жизни больных играет хорошая переносимость лечения. Основной целью лечения эпилепсии является создание баланса между эффективностью и переносимостью терапии. Авторы представляют обзор литературы по вопросам переносимости и безопасности антиэпилептической терапии. Сделан акцент на препараты вальпроевой кислоты, применяющиеся в лечении эпилепсии уже более 57 лет – за столь длительный период лечения вальпроат продолжает оставаться базовым препаратом с доказанно высокой эффективностью и хорошо изученными безопасностью и переносимостью. В том числе рассматриваются проблемы аггравации эпилепсии, связанной с приемом антиэпилептических препаратов, действие антиэпилептических препаратов на когнитивные функции, поведение и психическую сферу, актуальные вопросы переносимости и безопасности применения антиэпилептических препаратов у женщин репродуктивного возраста.

epilepsyepileptic seizureantiepileptic therapyantiepileptic drugvalproateefficacytolerabilitysafety of therapyэпилепсияэпилептический приступантиэпилептическая терапияантиэпилептический препаратвальпроатэффективностьпереносимостьбезопасность терапииAstakhova A.V., Ushkalova E.A. Adverse reactions caused by anticonvulsants in children. Bezopasnost lekarstv = Drug Safety 1997;(2):5–12. (In Russ.)Астахова А.В., Ушкалова Е.А. Побочные реакции, вызываемые противосудорожными средствами у детей. Безопасность лекарств 1997;(2):5–12.Zenkova A.L., Shatenshteyn A.A. Effect of antiepileptic drugs on cognitive functions of patients (literature review). Vestnik epileptologii = Bulletin of Epileptology 2014;(1–2):35– 42. (In Russ.)Зенкова А.Л., Шатенштейн А.А. Влияние антиэпилептических препаратов на когнитивные функции пациентов (обзор литературы). Вестник эпилептологии 2014;(1–2):35–42.Karlov V.A. Epilepsy in children and adults, men and women. Moscow: Meditsina, 2010. 720 p. (In Russ.)Карлов В.А. Эпилепсия у детей и взрослых женщин и мужчин. М.: Медицина, 2010. 720 с.Mukhin K.Yu., Glukhova L.Yu., Bobylova M.Yu. et al. Epileptic syndromes. Diagnosis and treatment. 4th edn. Moscow: “Sistemnye resheniya” LLC, 2018. 608 p. (In Russ.)Мухин К.Ю., Глухова Л.Ю., Бобылова М.Ю. и др. Эпилептические синдромы. Диагностика и терапия. 4-е изд-е. М.: ООО «Системные решения», 2018. 608 с.Mukhin K.Yu., Pylaeva O.A. Development of cognitive and mental disorders in epilepsy: the role of various factors associated with the disease and treatment (literature review and case reports). Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2017;12(3):7–33. (In Russ.) DOI: http://dx.doi.org/10.17650/2073- 8803-2017-12-3-7-33.Мухин К.Ю., Пылаева О.А. Формирование когнитивных и психических нарушений при эпилепсии: роль различных факторов, связанных с заболеванием и лечением (обзор литературы и описания клинических случаев). Русский журнал детской неврологии 2017;12(3):7–33. DOI: http://dx.doi.org/10.17650/2073- 8803-2017-12-3-7-33.Mukhin K.Yu., Pylaeva O.A., Borodin R.A., Mukhina L.N. Comparative efficacy and tolerability of monotherapy with Depakine Chronosphere, long-acting carbamazepine, and oxcarbazepine in patients with symptomatic and cryptogenic focal epilepsy (study of the Institute of Pediatric Neurology). Russkiy zhurnal detskoy nevrologii = Russian Journal of Child Neurology 2015;10(1):4–15. (In Russ.)]. DOI: 10.17650/2073-8803-2015-1-4-15.Мухин К.Ю., Пылаева О.А., Бородин Р.А., Мухина Л.Н. Сравнительная эффективность и переносимость монотерапии Депакином хроносфера, препаратами группы карбамазепина пролонгированного действия и окскарбазепином при симптоматической и криптогенной фокальной эпилепсии (исследование Института детской неврологии. Русский журнал детской неврологии 2015;10(1):4–15. DOI: 10.17650/2073-8803-2015-1-4-15.Mukhin K.Yu., Petrukhin A.S., Rykova E.A. Side effects of anticonvulsants in the treatment of idiopathic generalized epilepsy. Zhyrnal nevrologii i psikhiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry 1997;(7):25–31. (In Russ.)Мухин К.Ю., Петрухин А.С., Рыкова Е.А. Побочные эффекты антиконвульсантов при лечении идиопатической генерализованной эпилепсии. Журнал неврологии и психиатрии им. С.С. Корсакова 1997;(7):25–31.Provatorova M.A. Paradoxical effects of anti-epileptic drugs in the treatment of various forms of epilepsy. Summary of thesis … of candidate of medical sciences. Moscow, 2011. (In Russ.)Проваторова М.А. Парадоксальные эффекты антиэпилептических препаратов при лечении различных форм эпилепсии у детей. Автореф. … канд. мед. наук. М., 2011.Provatorova M.A., Voronkova K.V., Pylaeva O.A. et al. Aggravation of epilepsy. Nevrologicheskiy vestnik = Neurological Bulletin 2011;(2):86–91.Проваторова М.А., Воронкова К.В., Пылаева O.A. и др. Аггравация эпилепсии. Неврологический вестник 2011;(2):86–91.Pylaeva O.A., Mukhin K.Yu., Petrukhin A.S. Side effects of antiepileptic medication. Moscow: Granat, 2016. 232 p. (In Russ.)Пылаева О.А., Мухин К.Ю., Петрухин А.С. Побочные эффекты антиэпилептической терапии. М.: Гранат, 2016. 232 с.Pylaeva O.A., Voronkova K.V., Petrukhin A.S. Efficacy and safety of antiepileptic therapy in children (comparison of valproic acid and barbiturates). Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry 2004;(8):61–5. (In Russ.)Пылаева О.А., Воронкова К.В., Петрухин А.С. Эффективность и безопасность антиэпилептической терапии у детей (сравнительная оценка препаратов вальпроевой кислоты и барбитуратов). Журнал неврологии и психиатрии им. С.С. Корсакова 2004;(8):61–5.Pylaeva O.A. Safety of antiepileptic therapy: effect of barbiturates on mental state, behavior, and social adaptation. Vestnik epileptologii = Bulletin of Epileptology 2003;(1):8–11. (In Russ.)Пылаева О.А. Проблемы безопасности антиэпилептической терапии: влияние барбитуратов на психическое состояние, поведение и социальную адаптацию. Вестник эпилептологии 2003;(1):8–11.Petrukhin A.S., Mukhin K.Yu., Blagosklonova N.K., Alihanov A.A. Childhood epileptology. Moscow: Meditsina, 2000. Pp. 547–618. (In Russ.)Петрухин А.С., Мухин К.Ю., Благосклонова Н.К., Алиханов А.А. Эпилептология детского возраста. М.: Медицина, 2000. C. 547–618.Abou-Khalil B., Misulis K. Seizure management. In: Atlas of EEG, seizure semiology and management. 2nd edn. Oxford University Press, 2014. Pp. 269– 304.Aldenkamp A., Besag F., Gobbi G. et al. Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Adverse cognitive and behavioural effects of antiepileptic drugs in children. Epileptic Disord 2016. DOI: 10.1684/ epd.2016.0817.Altınöz A.E., Tosun Altınöz Ş., Güzel Biltekin B., Can Kaya M. Levetiracetam induced hypomania: a case report. Ther Adv Drug Saf 2019;10:2042098619876754. DOI: 10.1177/2042098619876754.Andersohn F., Schade R., Willich S.N. et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010;75:335–40.Arhan E., Serdaroğlu A., Hirfanoğlu T., Kurt G. Aggravation of seizures and status epilepticus after vagal nerve stimulation therapy: the first pediatric case and review of the literature. Childs Nerv Syst 2018. DOI: 10.1007/s00381-018-3806-x.Arts W.F. Newly diagnosed epilepsies: clinically relevant conclusions from global studies on outcome. In: Outcome of Childhood Epilepsies. Paris: J.L., 2013. Pp. 33–44.Arzimanoglou A. Treatment options in pediatric epilepsy syndromes. Epileptic Disord 2002;4(3):217–25.Arzimanoglou A., Guerrini R., Aicardi J. Aicardi’s epilepsy in children. 3rd edn. Philadelphia: Lippincott, 2004. Pp. 354– 386.Atif M., Azeem M., Sarwar M.R. Potential problems and recommendations regarding substitution of generic antiepileptic drugs: a systematic review of literature. Springerplus 2016;5:182. DOI: 10.1186/ s40064-016-1824-2.Banwari G.H., Parmar C.D., Kandre D.D. Alternative psychosis – is it a defined clinical entity? Indian J Psychol Med 2013;35:84–6.Barabas G., Matthews W.S. Barbiturate anticonvulsants as a cause of severe depression. Pediatrics 1988;82:284–5.Bertsche A., Neininger M.P., Dahse A.J. et al. Initial anticonvulsant monotherapy in routine care of children and adolescents: levetiracetam fails more frequently than valproate and oxcarbazepine due to a lack of effectiveness. Eur J Pediatr 2014;173(1):87–92.Born C., Dittmann S., Post R.M. et al. Newer prophylactic agents for bipolar disorder and their influence on suicidality. Arch Suicide Res 2005;9:301–6.Callaghan N., Kenny R.A., O’Neill B. et al. A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy. J Neurol Neurosurg Psychiatry 1985;48(7):639–44.Chadwick D., Marson T. Choosing a first drug treatment for epilepsy after SANAD: randomized controlled trials, systematic reviews, guidelines and treating patients. Epilepsia 2007;48(7):1259–63.Chen Z., Lusicic A., O’Brien T.J. et al. Psychotic disorders induced by antiepileptic drugs in people with epilepsy. Brain 2016;139(Pt 10):2668–78.Chowdhury A., Brodie M.J. Pharmacological outcomes in juvenile myoclonic epilepsy: Support for sodium valproate. Epilepsy Res 2016;119:62–6.Cook M., Shorvon S. The Pharmacokinetics and clinical therapeutics of antiepileptic drugs. In: Oxford textbook of epilepsy and epileptic seizures. Oxford: Oxford university press, 2013. Pp. 279–289.Coppola G. Treatment of partial seizures in childhood: an overview. CNS Drugs 2004;18:133–56.Cvetkovska E., Kuzmanovski I., Babunovska M. et al. Levetiracetaminduced seizure aggravation in patients with focal cortical dysplasia. Clin Neuropharmacol 2018;41(6):218–21. DOI: 10.1097/WNF.0000000000000304.De Silva M., MacArdle B., McGowan M. et al. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996;347(9003):709–13.Dussaule C., Bouilleret V. Psychiatric effects of antiepileptic drugs in adults. Geriatr Psychol Neuropsychiatr Vieil 2018;16(2):181–8. DOI: 10.1684/ pnv.2018.0733.Galappatthy P., Liyanage C.K., Lucas M.N. et al. Obstetric outcomes and effects on babies born to women treated for epilepsy during pregnancy in a resource limited setting: a comparative cohort study. BMC Pregnancy Childbirth 2018;18(1):230. DOI: 10.1186/s12884- 018-1857-3.Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev 2000;22:75–80.Glauser T., Ben-Menachem E., Bourgeois B. et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54(3):551–63. DOI: 10.1111/epi.12074.Guerrini R. Valproate as a mainstay of therapy for pediatric epilepsy. Paediatr Drugs 2006;8(2):113–29.Gustafson M.C., Ritter F.J., Frost M.D. et al. Behavioral and emotional effects of levetiracetam in children with intractable epilepsy. Epilepsia 2002;43:58–62.Hamoda H.M., Guild D.J., Gumlak S. et al. Association between attentiondeficit/hyperactivity disorder and epilepsy in pediatric populations. Expert Rev Neurother 2009;9:1747–54.Harden C.L. et al., American Academy of Neurology, American Epilepsy Society. Practice parameter update: management issues for women with epilepsy – focus on pregnancy (an evidence-ased review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73(2):133–41.Hirsch E., Genton P. Antiepileptic druginduced pharmacodynamic aggravation of seizures: does valproate have a lower potential? CNS Drugs 2003;17:633–40.Ijff D.M., van Veenendaal T.M., Debeijvan Hall M.H. et al. The cognitive profile of ethosuximide in children. Paediatr Drugs 2016;18(5):379–85.Iliescu С., Tarța-Arsene O., Craiu D. Valproic acid, polycystic ovary syndrome and the adolescent with epilepsy. Farmacia 2017;65:1–4.Johannessen Landmark C., Fløgstad I., Syvertsen M. et al. Treatment and challenges with antiepileptic drugs in patients with juvenile myoclonic epilepsy. Epilepsy Behav 2019;98(Pt A):110–6. DOI: 10.1016/j.yebeh.2019.05.021.Johannessen S.I., Ben-Menachem E. Management of focal-onset seizures. An update on drug treatment. Drugs 2006;66:1701–25.Josephson C.B., Engbers J.D.T., Jette N. et al. Prescription trends and psychiatric symptoms following first receipt of one of seven common antiepileptic drugs in general practice. Epilepsy Behav 2018;84:49–55. DOI: 10.1016/j. yebeh.2018.04.012.Kalinin V.V. Suicidality and antiepileptic drugs: is there a link? Drug Saf 2007;30:123–42.Kayani S., Sirsi D. The safety and tolerability of newer antiepileptic drugs in children and adolescents. J Cent Nerv Syst Dis 2012;4:51–63. DOI: 10.4137/JCNSD. S5097.Kossoff E.H., Bergey G.K., Freeman J.M. et al. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001;42:1611–3.Kwan P., Brodie M.J. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314–9.Kwan P., Brodie M.J. Refractory epilepsy: mechanisms and solutions. Expert Rev Neurother 2006;6(3):397–406.Liu J., Wang L.N., Wang YP. Topiramate monotherapy for juvenile myoclonic epilepsy. Cochrane Database Syst Rev 2015;12:CD010008. DOI: 10.1002/14651858.CD010008.pub2.Macfarlane A., Greenhalgh T. Sodium valproate in pregnancy: what are the risks and should we use a shared decision– making approach? BMC Pregnancy Childbirth 2018;18:200.Machado R.A., Espinosa A.G., Melendrez D. et al. Suicidal risk and suicide attempts in people treated with antiepileptic drugs for epilepsy. Seizure 2011;20:280–4.Marson A.G., Al-Kharusi A.M., Alwaidh M. et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1000–15.Moavero R., Santarone M.E., Galasso C., Curatolo P. Cognitive and behavioral effects of new antiepileptic drugs in pediatric epilepsy. Brain Dev 2017;39(6):464–9. DOI: 10.1016/j. braindev.2017.01.006.Montouris G. Safety of the newer antiepileptic drug oxcarbazepine during pregnancy. Curr Med Res Opin 2005;21(5):693–701.Mula M., Sander J.W. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf 2007;30:555–67.Nicolson A., Appleton R.E., Chadwick D.W., Smith D.F. The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies. J Neurol Neurosurg Psychiatry 2004;75(1):75–9.Olesen J.B., Hansen P.R., Erdal J. et al. Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiol Drug Saf 2010;19:518–24.Ornoy A. Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol 2009;28(1):1–10.Panayiotopoulos C.P. A clinical guide to epileptic syndromes and their treatment. 2nd edn. Springer, 2010. Pp. 45–49, 325– 335.Panayiotopoulos C.P. A сlinical guide to epileptic syndromes and their treatment. Springer, 2007. Pp. 155–184.Panayiotopoulos C.P. Syndromes of idiopathic generalized epilepsies not recognized by the International League Against Epilepsy. Epilepsia 2005;46 (Suppl 9):57–66.Pavlidis E., Rubboli G., Nikanorova M. et al. Encephalopathy with status epilepticus during sleep (ESES) induced by oxcarbazepine in idiopathic focal epilepsy in childhood. Funct Neurol 2015;30(2):139–41.Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002;16:695–724.Perucca E., Gram L., Avanzini G. et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998;39:5–17.Pinckaers F.M.E., Boon M.E., Majoie M.H.J.M. Risk factors predisposing to psychotic symptoms during study. Epilepsy Behav 2019;100(Pt A):106344. DOI: 10.1016/j. yebeh.2019.05.039.Sankar R., Holmes G. L. Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug–associated neurobehavioral adverse effects. J Child Neurol 2004;19:6–14.Schiemann-Delgado J., Yang H., de la Loge C. et al. A Long-term open-label extension study assessing cognition and behavior, tolerability, safety, and efficacy of adjunctive levetiracetam in children aged 4 to 16 years with partial–onset seizures. J Child Neur 2012;27:80–9.Schubert R. Attention deficit disorder and epilepsy. Pediatr Neurol 2005;32:1–10.Sima I.P., Page B.P. Management of epilepsy during pregnancy: an update. Ther Adv Neurol Disord 2016;9(2):118– 29. DOI: 10.1177/1756285615623934.Somerville E.R. Levetiracetam-induced seizure aggravation in patients with focal cortical dysplasia. Clin Neuropharmacol 2019;42(4):146. DOI: 10.1097/ WNF.0000000000000349.Stephen L.J. Drug treatment of epilepsy in elderly people: focus on valproic аcid. Drugs Aging 2003;20(2):141–52.Thomas P., Valton L., Genton P. Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy. Brain 2006;129:1281–92.Toepfer M., Sitter T., Lochmuller H. et al. Drug-induced systemic lupus erythematosus after 8 years of treatment with carbamazepine. Eur J Clin Pharmacol 1998;54:193–4.Trimble M.R. Interictal psychoses of epilepsy. In: Advances in Neurology. Vol. 55. New York: Raven Press, 1991. Pp. 143–152.Trimble M.R., Schmitz B. Seizures, affective disorders and anticonvulsant drugs. Guildford: Clarus Press Ltd, 2002.Trinka E., Marson A.G., Van Paesschen W. et al. KOMET: an unblinded, randomized, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry 2013;84:1138–47.Turan A.B., Seferoglu M., Taskapilioglu O. et al. Vulnerability of an epileptic case to psychosis: sodium valproate with lamotrigine, forced normalization, postictal psychosis or all? Neurol Sci 2012;33:1161–3.Vajda F.J., O’Brien T.J, Lander C.M. et al. The teratogenicity of the newer antiepileptic drugs – an update. Acta Neurol Scand 2014;130(4):234–8. DOI: 10.1111/ane.12280.Van Veenendaal T.M., Ijff D.M., Aldenkamp A.P. et al. Glutamate concentrations vary with antiepileptic drug use and mental slowing. Epilepsy Behav 2016;64(Pt A):200–5. DOI: 10.1016/j. yebeh.2016.08.027.Vossler D.G. Comparative risk of major congenital malformations with 8 different antiepileptic drugs: a prospective cohort study of the EURAP Registry. Epilepsy Curr 2019;19(2):83–5. DOI: 10.1177/1535759719835353.Williams A.E., Giust J.M., Kronenberger W.G., Dunn D.W. Epilepsy and attention-deficit hyperactivity disorder: links, risks, and challenges. Neuropsychiatr Dis Treat 2016;12:287–96. DOI: 10.2147/NDT.S81549.Wolf P. Acute behavioral symptomatology at disappearance of epileptiform EEG abnormality. Paradoxical or “forced” normalization. Adv Neurol 1991; 55:127–42.Wolf P. Epileptic seizures and syndromes. London: J Libbey, 1994.Wyllie E. Wyllie’s treatment of epilepsy: principles and practice. 6th edn. 2015. 2088 p.Yang M.T., Lee W.T., Chu L.W. et al. Antiepileptic drugs-induced de novo absence seizures. Brain Dev 2003;25:51–6.Yerevanian B.I., Koek R.J., Mintz J. Lithium, anticonvulsants and suicidal behavior in bipolar disorder. J Affect Disord 2003;73:223–8.