Clinical efficacy and safety study of agomelatine combined with eszopiclone in the treatment of epilepsy complicated by insomnia_Journal of Epilepsy

Authors：

BI Jinyu ¹ , DU Taotao ¹ , LUO Chenyu ¹ ,  SUN Meizhen ²

1. The First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, China;
2. Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan 030001, China;

Corresponding author：

SUN Meizhen, Email: sunmeizhen213@126.com

Keywords：

Epilepsy; Insomnia; Agomelatine; Eszopiclone; Depression; Anxiety

DOI：

10.7507/2096-0247.202303010

Video：

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Objective To investigate the clinical effect and safety study of agomelatine combined with eszopiclone in the treatment of epilepsy complicated by insomnia. Methods 69 epilepsy complicated by insomnia patients were collected in the outpatient of the Department of Neurology, the First Affiliated Hospital of Shanxi Medical University from December 2021 to October 2022. Patients were randomly divided into control group (34 cases) and observation group (35 cases) Patients in control group were given eszopiclone, 1.5 ~ 3 mg (3 ~ 5 times/week). Patients in observation group were given agomelatine 25 mg (1 time/day) and eszopiclone 1.5 ~ 3 mg (3 ~ 5 times/week). Patients in both groups maintained their original anti-seizure medications treatment regimen for 12 weeks during the study. Pittsburgh sleep quality index (PSQI), Insomnia severity scale (ISI), Patient health questionnaire-9 (PHQ-9) and Generalized anxiety disorder-7 (GAD-7) were used to compare differences in subjective sleep quality, insomnia severity, depression and anxiety symptoms before treatment and at the end of 4 and 12 weeks of treatment. The change of seizure frequency before and after treatment was statistically evaluated to assess epilepsy control. The adverse effects after medication were recorded in both groups. Results After 4 weeks and 12 weeks of treatment, the scores of PSQI, ISI, PHQ-9 and GAD-7 of both groups were significantly lower than those before treatment, and the scores of PSQI, ISI, PHQ-9 and GAD-7 in the combined group at the 4th week and 12 weeks after treatment were significantly lower than those in the single-drug group (P<0.05). The incidence of adverse reactions was 13.33% in the single-agent group and 15.63% in the combined group. Conclusions Agomelatine combined with eszopiclone improve subjective sleep quality, insomnia severity, depression and anxiety symptoms of patients more significantly.

Citation： BI Jinyu, DU Taotao, LUO Chenyu, SUN Meizhen. Clinical efficacy and safety study of agomelatine combined with eszopiclone in the treatment of epilepsy complicated by insomnia. Journal of Epilepsy, 2023, 9(4): 287-293. doi: 10.7507/2096-0247.202303010 Copy

1.	Wang WZ, Wu JZ, Wang DS, et al. The prevalence and treatment gap in epilepsy in China: an ILAE/IBE/WHO study. Neurology, 2003, 60(9): 1544-1545.
2.	van Golde EG, Gutter T, de Weerd AW. Sleep disturbances in people with epilepsy; prevalence, impact and treatment. Sleep Med Rev, 2011, 15(6): 357-368.
3.	Nobili L, Frauscher B, Eriksson S, et al. Sleep and epilepsy: a snapshot of knowledge and future research lines. J Sleep Res, 2022, 31(4): e13622.
4.	Moore JL, Carvalho DZ, St Louis EK, et al. Sleep and epilepsy: a focused review of pathophysiology, clinical syndromes, co-morbidities, and therapy. Neurotherapeutics, 2021, 18(1): 170-180.
5.	Chakravarty K, Shukla G, Poornima S, et al. Effect of sleep quality on memory, executive function, and language performance in patients with refractory focal epilepsy and controlled epilepsy versus healthy controls - a prospective study. Epilepsy Behav, 2019, 92: 176-183.
6.	丁玎, 洪震, 丁美萍, 等. 癫痫共患睡眠障碍诊断治疗的中国专家共识. 癫痫杂志, 2019, 5(06): 417-423.
7.	Liguori C, Toledo M, Kothare S. Effects of anti-seizure medications on sleep architecture and daytime sleepiness in patients with epilepsy: A literature review. Sleep Med Rev, 2021, 60: 101559.
8.	Rios P, Cardoso R, Morra D, et al. Comparative effectiveness and safety of pharmacological and non-pharmacological interventions for insomnia: an overview of reviews. Syst Rev, 2019, 8(1): 281.
9.	Koffel EA, Koffel JB, Gehrman PR. A meta-analysis of group cognitive behavioral therapy for insomnia. Sleep Med Rev, 2015, 19: 6-16.
10.	Rösner S, Englbrecht C, Wehrle R, et al. Eszopiclone for insomnia. Cochrane Database Syst Rev, 2018, 10(10): CD010703.
11.	Guardiola-Lemaitre B, De Bodinat C, Delagrange P, et al. Agomelatine: mechanism of action and pharmacological profile in relation to antidepressant properties. Br J Pharmacol, 2014, 171(15): 3604-3619.
12.	中华医学会神经病学分会, 中华医学会神经病学分会睡眠障碍学组. 中国成人失眠诊断与治疗指南(2017版). 中华神经科杂志, 2018, 51(5): 324-335.
13.	Al-Biltagi MA. Childhood epilepsy and sleep. World J Clin Pediatr, 2014, 3(3): 45-53.
14.	Macêdo PJOM, Oliveira PS, Foldvary-Schaefer N, et al. Insomnia in people with epilepsy: a review of insomnia prevalence, risk factors and associations with epilepsy-related factors. Epilepsy Res, 2017, 135: 158-167.
15.	Nielsen S. Benzodiazepines. Curr Top Behav Neurosci, 2017, 34: 141-159.
16.	Matheson E, Hainer BL. Insomnia: pharmacologic therapy. Am Fam Physician, 2017, 96(1): 29-35.
17.	Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an american academy of sleep medicine clinical practice guideline. J Clin Sleep Med, 2017, 13(2): 307-349.
18.	Huedo-Medina TB, Kirsch I, Middlemass J, et al. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ, 2012, 345: e8343.
19.	Rosenberg R, Caron J, Roth T, et al. An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults. Sleep Med, 2005, 6(1): 15-22.
20.	Tchekalarova J, Kortenska L, Ivanova N, et al. Agomelatine treatment corrects impaired sleep-wake cycle and sleep architecture and increases MT(1) receptor as well as BDNF expression in the hippocampus during the subjective light phase of rats exposed to chronic constant light. Psychopharmacology (Berl), 2020, 237(2): 503-518.
21.	Mi WF, Tabarak S, Wang L, et al. Effects of agomelatine and mirtazapine on sleep disturbances in major depressive disorder: evidence from polysomnographic and resting-state functional connectivity analyses. Sleep, 2020, 43(11): 384-386.
22.	Porteous M, Fogel S, Ray L, et al. Increased spindle density correlates with sleep continuity improvements following an eight-week course of a melatonin agonist in people with depression: A proof-of-concept study with agomelatine. Eur J Neurosci, 2021, 54(3): 5112-5119.
23.	Zajecka J, Schatzberg A, Stahl S, et al. Efficacy and safety of agomelatine in the treatment of major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol, 2010, 30(2): 135-144.
24.	Arango C, Buitelaar JK, Fegert JM, et al. Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries. Lancet Psychiatry, 2022, 9(2): 113-124.
25.	Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet, 2018, 391(10128): 1357-1366.
26.	魏昆岭, 孙秀丽, 张彦恒, 等. 阿戈美拉汀片与帕罗西汀片治疗抑郁症伴失眠症状的临床研究. 中国临床药理学杂志, 2019, 35(23): 3009-3012.
27.	梁炜, 张迎黎, 张红梅. 固定剂量阿戈美拉汀短期治疗广泛性焦虑障碍的临床对照试验. 中国新药与临床杂志, 2015, 34(07): 544-547.
28.	Aguiar CC, Almeida AB, Araújo PV, et al. Anticonvulsant effects of agomelatine in mice. Epilepsy Behav, 2012, 24(3): 324-328.
29.	Ethemoglu MS, Kutlu S, Seker FB, et al. Effects of agomelatine on electrocorticogram activity on penicillin-induced seizure model of rats. Neurosci Lett, 2019, 690: 120-125.
30.	Azim MS, Agarwal NB, Vohora D. Effects of agomelatine on pentylenetetrazole-induced kindling, kindling-associated oxidative stress, and behavioral despair in mice and modulation of its actions by luzindole and 1-(m-chlorophenyl) piperazine. Epilepsy Behav, 2017, 72: 140-144.
31.	Tchekalarova J, Atanasova D, Nenchovska Z, et al. Agomelatine protects against neuronal damage without preventing epileptogenesis in the kainate model of temporal lobe epilepsy. Neurobiol Dis, 2017, 104: 1-14.
32.	Borchert JS, Wang B, Ramzanali M, et al. Adverse events due to insomnia drugs reported in a regulatory database and online patient reviews: comparative study. J Med Internet Res, 2019, 21(11): e13371.
33.	Oliva V, Lippi M, Paci R, et al. Gastrointestinal side effects associated with antidepressant treatments in patients with major depressive disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry, 2021, 109: 110266.

1. Wang WZ, Wu JZ, Wang DS, et al. The prevalence and treatment gap in epilepsy in China: an ILAE/IBE/WHO study. Neurology, 2003, 60(9): 1544-1545.
2. van Golde EG, Gutter T, de Weerd AW. Sleep disturbances in people with epilepsy; prevalence, impact and treatment. Sleep Med Rev, 2011, 15(6): 357-368.
3. Nobili L, Frauscher B, Eriksson S, et al. Sleep and epilepsy: a snapshot of knowledge and future research lines. J Sleep Res, 2022, 31(4): e13622.
4. Moore JL, Carvalho DZ, St Louis EK, et al. Sleep and epilepsy: a focused review of pathophysiology, clinical syndromes, co-morbidities, and therapy. Neurotherapeutics, 2021, 18(1): 170-180.
5. Chakravarty K, Shukla G, Poornima S, et al. Effect of sleep quality on memory, executive function, and language performance in patients with refractory focal epilepsy and controlled epilepsy versus healthy controls - a prospective study. Epilepsy Behav, 2019, 92: 176-183.
6. 丁玎, 洪震, 丁美萍, 等. 癫痫共患睡眠障碍诊断治疗的中国专家共识. 癫痫杂志, 2019, 5(06): 417-423.
7. Liguori C, Toledo M, Kothare S. Effects of anti-seizure medications on sleep architecture and daytime sleepiness in patients with epilepsy: A literature review. Sleep Med Rev, 2021, 60: 101559.
8. Rios P, Cardoso R, Morra D, et al. Comparative effectiveness and safety of pharmacological and non-pharmacological interventions for insomnia: an overview of reviews. Syst Rev, 2019, 8(1): 281.
9. Koffel EA, Koffel JB, Gehrman PR. A meta-analysis of group cognitive behavioral therapy for insomnia. Sleep Med Rev, 2015, 19: 6-16.
10. Rösner S, Englbrecht C, Wehrle R, et al. Eszopiclone for insomnia. Cochrane Database Syst Rev, 2018, 10(10): CD010703.
11. Guardiola-Lemaitre B, De Bodinat C, Delagrange P, et al. Agomelatine: mechanism of action and pharmacological profile in relation to antidepressant properties. Br J Pharmacol, 2014, 171(15): 3604-3619.
12. 中华医学会神经病学分会, 中华医学会神经病学分会睡眠障碍学组. 中国成人失眠诊断与治疗指南(2017版). 中华神经科杂志, 2018, 51(5): 324-335.
13. Al-Biltagi MA. Childhood epilepsy and sleep. World J Clin Pediatr, 2014, 3(3): 45-53.
14. Macêdo PJOM, Oliveira PS, Foldvary-Schaefer N, et al. Insomnia in people with epilepsy: a review of insomnia prevalence, risk factors and associations with epilepsy-related factors. Epilepsy Res, 2017, 135: 158-167.
15. Nielsen S. Benzodiazepines. Curr Top Behav Neurosci, 2017, 34: 141-159.
16. Matheson E, Hainer BL. Insomnia: pharmacologic therapy. Am Fam Physician, 2017, 96(1): 29-35.
17. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an american academy of sleep medicine clinical practice guideline. J Clin Sleep Med, 2017, 13(2): 307-349.
18. Huedo-Medina TB, Kirsch I, Middlemass J, et al. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ, 2012, 345: e8343.
19. Rosenberg R, Caron J, Roth T, et al. An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults. Sleep Med, 2005, 6(1): 15-22.
20. Tchekalarova J, Kortenska L, Ivanova N, et al. Agomelatine treatment corrects impaired sleep-wake cycle and sleep architecture and increases MT(1) receptor as well as BDNF expression in the hippocampus during the subjective light phase of rats exposed to chronic constant light. Psychopharmacology (Berl), 2020, 237(2): 503-518.
21. Mi WF, Tabarak S, Wang L, et al. Effects of agomelatine and mirtazapine on sleep disturbances in major depressive disorder: evidence from polysomnographic and resting-state functional connectivity analyses. Sleep, 2020, 43(11): 384-386.
22. Porteous M, Fogel S, Ray L, et al. Increased spindle density correlates with sleep continuity improvements following an eight-week course of a melatonin agonist in people with depression: A proof-of-concept study with agomelatine. Eur J Neurosci, 2021, 54(3): 5112-5119.
23. Zajecka J, Schatzberg A, Stahl S, et al. Efficacy and safety of agomelatine in the treatment of major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol, 2010, 30(2): 135-144.
24. Arango C, Buitelaar JK, Fegert JM, et al. Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries. Lancet Psychiatry, 2022, 9(2): 113-124.
25. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet, 2018, 391(10128): 1357-1366.
26. 魏昆岭, 孙秀丽, 张彦恒, 等. 阿戈美拉汀片与帕罗西汀片治疗抑郁症伴失眠症状的临床研究. 中国临床药理学杂志, 2019, 35(23): 3009-3012.
27. 梁炜, 张迎黎, 张红梅. 固定剂量阿戈美拉汀短期治疗广泛性焦虑障碍的临床对照试验. 中国新药与临床杂志, 2015, 34(07): 544-547.
28. Aguiar CC, Almeida AB, Araújo PV, et al. Anticonvulsant effects of agomelatine in mice. Epilepsy Behav, 2012, 24(3): 324-328.
29. Ethemoglu MS, Kutlu S, Seker FB, et al. Effects of agomelatine on electrocorticogram activity on penicillin-induced seizure model of rats. Neurosci Lett, 2019, 690: 120-125.
30. Azim MS, Agarwal NB, Vohora D. Effects of agomelatine on pentylenetetrazole-induced kindling, kindling-associated oxidative stress, and behavioral despair in mice and modulation of its actions by luzindole and 1-(m-chlorophenyl) piperazine. Epilepsy Behav, 2017, 72: 140-144.
31. Tchekalarova J, Atanasova D, Nenchovska Z, et al. Agomelatine protects against neuronal damage without preventing epileptogenesis in the kainate model of temporal lobe epilepsy. Neurobiol Dis, 2017, 104: 1-14.
32. Borchert JS, Wang B, Ramzanali M, et al. Adverse events due to insomnia drugs reported in a regulatory database and online patient reviews: comparative study. J Med Internet Res, 2019, 21(11): e13371.
33. Oliva V, Lippi M, Paci R, et al. Gastrointestinal side effects associated with antidepressant treatments in patients with major depressive disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry, 2021, 109: 110266.

Journal of Epilepsy

Clinical efficacy and safety study of agomelatine combined with eszopiclone in the treatment of epilepsy complicated by insomnia

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