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Epilepsy and paroxysmal conditions

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Exogenous melatonin as a disease-modifying therapy for epilepsy

https://doi.org/10.17749/2077-8333.2019.11.2.124-141

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Abstract

Melatonin - the most well studied factor of the circadian rhythm - attracts much intereset in regard to a disease-modifying therapy for epilepsy. In some forms of epilepsy, circadian dysrhythmias and sleep disorders can trigger the development of epileptic seizures, while in others - seizures develop from the REM-phase of sleep.

The aim is to review and analyze studies on the efficacy and safety of exogenous melatonin as an additional medication for disease-modifying therapy in pediatric and adult patients with epilepsy.

Materials and methods. The search was conducted for Russian and English articles reflecting the results of studies on the efficacy and safety of exogenous melatonin in patients with epilepsy. We used the following databases: ELibrary.ru, Web of Science, Scopus, Clinical Case, PubMed, Cochrane Database of Systematic Reviews. The search was carried out using the keywords: melatonin, epilepsy, epileptic syndrome, disease-modifying therapy, children, adolescents, adults, safety, efficacy, reduction of seizures, adverse drug reactions, quality of life. The following materials were included in the search: full-text articles in Russian and English; original research papers; Cochrane reviews; clinical observations; publication dates - from 2003 to 2018. We did not reviwed: abstracts; theses; monographs; handbooks; textbooks; materials published before 2003. In total we found 986 publications; of those, 114 met the inclusion criteria.

Results. Clinical studies on the efficacy and safety of exogenous melatonin in a disease-modifying therapy for epilepsy in children and adults are rare, conducted in small groups of patients, and differ in their design. These findings do not allow recommending melatonin, at the present time, for widespread use in the routine clinical treatment of epilepsia. Notably, determining the optimal daily dose of exogenous melatonin is rather difficult because this drug has both proconvulsive and anticonvulsant effects. Therefore, such a disease-modifying therapy requires a personalized approach to achieve a balance between these two actions of melatonin.

Conclusion. The role of exogenous melatonin as a treatment modality in epilepsy remains unclear, although this approach is considered possible for disease-modifying therapy. Large-scale clinical studies on the efficacy and safety of exogenous melatonin in epilepsy are needed. Currently, the use of exogenous melatonin in epilepsy is not regulated by law.

About the Authors

P. V. Moskaleva
Bekhterev National Medical Research Center of Psychiatry and Neurology
Russian Federation

Polina V. Moskaleva - MD, Neurologist, Department of Personalized Psychiatry and Neurology, Elibrary ID: 996170; SPIN-код: 9097-3068; Researcher ID: U-7810-2018; Scopus ID: 57201523579.

3 Bekhtereva Str., Saint-Petersburg 192019



N. A. Shnayder
Bekhterev National Medical Research Center of Psychiatry and Neurology
Russian Federation

Natalia A. Shnayder - MD, PhD, D. Med. Sci., Professor, Leading Researcher, Department of Personalized Psychiatry and Neurology, Elibrary ID: 185359; SPIN-код: 6517-0279; Researcher ID: M-7084-2014; Scopus ID: 24503222300

3 Bekhtereva Str., Saint-Petersburg 192019



N. G. Neznanov
Bekhterev National Medical Research Center of Psychiatry and Neurology
Russian Federation

Nikolai G. Neznanov- MD, PhD, D. Med. Sci., Director, Head of the Department of Geriatric Psychiatry. Elibrary ID: 108604; SPIN-код: 9772-0024; Researcher ID: U-1562-2017; Scopus ID: 35593613200.

3 Bekhtereva Str., Saint-Petersburg 192019



D. V. Dmitrenko
Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University
Russian Federation

Diana V. Dmitrenko - MD, PhD, D. Med. Sci., Head, Center for Neurology, Epileptology and Neurogenetics, University Hospital; Head of the Department of Medical Genetics and Clinical Neurophysiology, IPO, Voino-Yasenetsky SMU, City of Krasnoyarsk. Elibrary ID: 614958; SPIN-код: 9180-6623; Researcher ID: H-7787-2016; Scopus ID: 55413907300.

1 Partizana Zheleznyaka Str., Krasnoyarsk 660022



V. A. Golokov
Republic Hospital No. 1 of National Center of Medicine
Russian Federation

Vladislav A. Golokov - MD, PhD, Neurologist, Women’s Health Clinic, Yakut City Clinical Hospital. Elibrary ID: 838987; SPIN-код: 8468-4325.

4 Sergelyehskoye Highway Str., Yakutsk 677000, Republic of Sakha (Yakutia)



R. F. Nasyrova
Bekhterev National Medical Research Center of Psychiatry and Neurology
Russian Federation

Regina F. Nasyrova - MD, PhD, D. Med. Sci., Chief Researcher, Head of Department of Personalized Psychiatry and Neurology, Elibrary ID: 551543; SPIN-код: 3799-0099; Researcher ID: B-1259-2014; Scopus ID: 15769218400

3 Bekhtereva Str., Saint-Petersburg 192019



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92. Gupta M., Aneja S., Kohli K. Add-on melatonin improves sleep behavior in children with epilepsy: randomized, double-blind, placebo-controlled trial. J Child Neurol. 2005; 20 (2): 112-115. DOI: 10.1177/08830738050200020501.

93. Gupta M., Gupta Y.K., Agarwal S., Aneja S., Kohli K. A randomized, double-blind, placebo controlled trial of melatonin add-on therapy in epileptic children on valproate monotherapy: effect on glutathione peroxidase and glutathione reductase enzymes. Br J Clin Pharmacol. 2004; 58 (5): 542-547. DOI: 10.1111/j.1365-2125.2004.02210.x.

94. Solowiej E., Sobaniec W. The effect of antiepileptic drug therapy on antioxidant enzyme activity and serum lipid peroxidation in young patients with epilepsy. NeurolNeurochirPol. (in Polish). 2003; 37 (5): 991-1003. PubMed PMID: 15174247.

95. Hancock E., O’Callaghan F., Osborne J.P. Effect of melatonin dosage on sleep disorder in tuberous sclerosis complex. Journal of Child Neurology. 2005; 20 (1): 78-80. DOI: 10.1177/08830738050200011302.

96. Coppola G., Iervolino G., Mastrosimone M., La Torre G., Ruiu F., Pascotto A. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Brain Dev. 2004; 26 (6): 373-376. DOI: 10.1016/S0387-7604(03)00197-9.

97. Jain S.V., Horn P.S., Simakajornboon N., Beebe D.W., Holland K., Byars A.W., Glauser T.A. Melatonin improves sleep in children with epilepsy: a randomized, double-blind, crossover study. Sleep Med. 2015; 16 (5): 637-644. DOI: 10.1016/j.sleep.2015.01.005.

98. Molina-Carballo A., Munoz-Hoyos A., Rodriguez-Cabezas T., Acuna-Castroviejo D. Day-night variations in melatonin secretion by the pineal gland during febrile and epileptic convulsions in children. Psychiatry Res. 1994; 52 (3): 273-283. DOI: 10.1016/0165-1781(94)90073-6.

99. Saracz J., Rosdy B. Effect of melatonin on intractable epilepsies. Orv Hetil. (in Hungarian). 2004; 145 (51): 2583-2587. PubMed PMID: 15715292.

100. Uberos J., Augustin-Morales M.C., Molina Carballo A., Florido J., Narbona E., Munoz-Hoyos A. Normalization of the sleep-wake pattern and melatonin and 6-sulphatoxy-melatonin levels after a therapeutic trial with melatonin in children with severe epilepsy. J Pineal Res. 2011; 50 (2): 192-196. DOI: 10.1111/j.1600-079X.2010.00828.

101. Elkhayat H.A., Hassanein S.M., Tomoum H.Y., Abd-Elhamid I.A., Asaad T., Elwakkad A.S. Melatonin and sleep-related problems in children with intractable epilepsy. Pediatr Neurol. 2010; 42 (4): 249-254. DOI: 10.1016/j.pediatrneurol.2009.11.002.

102. Goldberg-Stern H., Oren H., Peled N., Garty B.Z. Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study. J Child Neurol. 2012; 27 (12): 1524-1528. DOI: 10.1177/0883073811435916.

103. McArthur A.J., Budden S.S. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol. 1998; 40 (3): 186-192. DOI: 10.1111/j.1469-8749.1998.tb15445.x.

104. Myers K.A., Davey M.J., Ching M., Ellis C., Grinton B.E., Roten A., Lightfoot P.A., Scheffer I.E. Randomized Controlled Trial of Melatonin for Sleep Disturbance in Dravet Syndrome: The DREAMS Study. J Clin Sleep Med. 2018; 14 (10): 1697-1704. DOI: 10.5664/jcsm.7376.

105. Jain S., Besag F.M. Does melatonin affect epileptic seizures? Drug Saf. 2013; 36 (4): 207-215. DOI: 10.1007/s40264-013-0033-y.

106. Banach M., Gurdziel E., J^drych M., Borowicz K.K. Melatonin in experimental seizures and epilepsy. Pharmacol Rep. 2011; 63 (1): 1-11. PubMed PMID: 21441606.

107. Tchekalarova J., Moyanova S., Fusco A.D., Ngomba R.T. The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders. Brain Res Bull. 2015; 119 (Pt A): 80-92. DOI: 10.1016/j.brainresbull.2015.08.006.

108. Stewart L.S., Leung L.S. Hippocampal melatonin receptors modulate seizure threshold. Epilepsia. 2005; 46 (4): 473-480. DOI: 10.1111/j .0013-9580.2005.30204.x.

109. Musshoff U., Speckmann E.J. Diurnal actions of melatonin on epileptic activity in hippocampal slices of rats. Life Sci. 2003; 73 (20): 2603-2610. DOI: 10.1016/S0024-3205(03)00614-3.

110. Schapel G.J., Beran R.G., Kennaway D.L., McLoughney J., Matthews C.D. Melatonin response in active epilepsy. Epilepsia. 1995; 36 (1): 75-78. DOI: 0.1111/j.1528-1157.1995.tb01669.x.

111. Sandyk R., Tsagas N., Anninos P.A. Melatonin as a proconvulsive hormone in humans. Int J Neurosci. 1992; 63 (1-2): 125-135. PubMed PMID: 1342024.

112. Yal yn O., Arman F., Erdogan F., Kula M. A comparison of the circadian rhythms and the levels of melatonin in patients with diurnal and nocturnal complex partial seizures. Epilepsy Behav. 2006; 8 (3): 542-546. DOI: 10.1016/j.yebeh.2005.12.015.

113. Fauteck J.D., Bockmann J., Bockers T.M., Wittkowski W., Kohling R., Lucke A., Straub H., Speckmann E.J., Tuxhorn I., Wolf P., et al. Melatonin reduces low-Mg2+ epileptiform activity in human temporal slices. Exp Brain Res. 1995; 107 (2): 321-5. PubMed PMID: 8773250.

114. Yuksel A., Cengiz M., Seven M., Ulutin T. Erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children with valproate and carbamazepine monotherapy. J Basic Clin Physiol Pharmacol. 2000; 11 (1): 73-81. PubMed PMID: 10851665.

115. Manni R., De Icco R., Cremascoli R., Ferrera G., Furia F., Zambrelli E., Canevini M.P., Terzaghi M. Circadian phase typing in idiopathic generalized epilepsy: Dimlight melatonin onset and patterns of melatonin secretion-Semicurve findings in adult patients. Epilepsy Behav. 2016; 61: 132-137. DOI: 10.1016/j.yebeh.2016.05.019.

116. Uberos J., Augustin-Morales M.C., Molina Carballo A., Florido J., Narbona E., Munoz-Hoyos A. Normalization of the sleep-wake pattern and melatonin and 6-sulphatoxy-melatonin levels after a therapeutic trial with melatonin in children with severe epilepsy. J Pineal Res. 2011; 50 (2): 192-196. DOI: 10.1111/j.1600-079X.2010.00828.

117. Elkhayat H.A., Hassanein S.M., Tomoum H.Y., Abd-Elhamid I.A., Asaad T., Elwakkad A.S. Melatonin and sleep-related problems in children with intractable epilepsy. Pediatr Neurol. 2010; 42 (4): 249-254. DOI: 10.1016/j.pediatrneurol.2009.11.002.

118. Goldberg-Stern H., Oren H., Peled N., Garty B.Z. Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study. J Child Neurol. 2012; 27 (12): 1524-1528. DOI: 10.1177/0883073811435916.

119. McArthur A.J., Budden S.S. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol. 1998; 40 (3): 186-192. DOI: 10.1111/j.1469-8749.1998.tb15445.x.

120. Myers K.A., Davey M.J., Ching M., Ellis C., Grinton B.E., Roten A., Lightfoot P.A., Scheffer I.E. Randomized Controlled Trial of Melatonin for Sleep Disturbance in Dravet Syndrome: The DREAMS Study. J Clin Sleep Med. 2018; 14 (10): 1697-1704. DOI: 10.5664/jcsm.7376.

121. Jain S., Besag F.M. Does melatonin affect epileptic seizures? Drug Saf. 2013; 36 (4): 207-215. DOI: 10.1007/s40264-013-0033-y.

122. Banach M., Gurdziel E., J^drych M., Borowicz K.K. Melatonin in experimental seizures and epilepsy. Pharmacol Rep. 2011; 63 (1): 1-11. PubMed PMID: 21441606.

123. Tchekalarova J., Moyanova S., Fusco A.D., Ngomba R.T. The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders. Brain Res Bull. 2015; 119 (Pt A): 80-92. DOI: 10.1016/j.brainresbull.2015.08.006.

124. Stewart L.S., Leung L.S. Hippocampal melatonin receptors modulate seizure threshold. Epilepsia. 2005; 46 (4): 473-480. DOI: 10.1111/j.0013-9580.2005.30204.x.

125. Musshoff U., Speckmann E.J. Diurnal actions of melatonin on epileptic activity in hippocampal slices of rats. Life Sci. 2003; 73 (20): 2603-2610. DOI: 10.1016/S0024-3205(03)00614-3.

126. Schapel G.J., Beran R.G., Kennaway D.L., McLoughney J., Matthews C.D. Melatonin response in active epilepsy. Epilepsia. 1995; 36 (1): 75-78. DOI: 0.1111/j.1528-1157.1995.tb01669.x.

127. Sandyk R., Tsagas N., Anninos P.A. Melatonin as a proconvulsive hormone in humans. Int J Neurosci. 1992; 63 (1-2): 125-135. PubMed PMID: 1342024.

128. Yal yn O., Arman F., Erdogan F., Kula M. A comparison of the circadian rhythms and the levels of melatonin in patients with diurnal and nocturnal complex partial seizures. Epilepsy Behav. 2006; 8 (3): 542-546. DOI: 10.1016/j.yebeh.2005.12.015.

129. Fauteck J.D., Bockmann J., Bockers T.M., Wittkowski W., Kohling R., Lucke A., Straub H., Speckmann E.J., Tuxhorn I., Wolf P., et al. Melatonin reduces low-Mg2+ epileptiform activity in human temporal slices. Exp Brain Res. 1995; 107 (2): 321-5. PubMed PMID: 8773250.

130. Yuksel A., Cengiz M., Seven M., Ulutin T. Erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children with valproate and carbamazepine monotherapy. J Basic Clin Physiol Pharmacol. 2000; 11 (1): 73-81. PubMed PMID: 10851665.

131. Manni R., De Icco R., Cremascoli R., Ferrera G., Furia F., Zambrelli E., Canevini M.P., Terzaghi M. Circadian phase typing in idiopathic generalized epilepsy: Dimlight melatonin onset and patterns of melatonin secretion-Semicurve findings in adult patients. Epilepsy Behav. 2016; 61: 132-137. DOI: 10.1016/j.yebeh.2016.05.019.


For citation:


Moskaleva P.V., Shnayder N.A., Neznanov N.G., Dmitrenko D.V., Golokov V.A., Nasyrova R.F. Exogenous melatonin as a disease-modifying therapy for epilepsy. Epilepsy and paroxysmal conditions. 2019;11(2):124-141. (In Russ.) https://doi.org/10.17749/2077-8333.2019.11.2.124-141

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