Valproic acid and weight gain in patients receiving antiepileptic treatment: a systematic review
DOI:
https://doi.org/10.5281/zenodo.7843532Keywords:
antiepileptics, valproic acid, weight gain, leptin, insulinAbstract
Introduction: valproic acid is a drug used in the treatment of various diseases, including epilepsy. Although it is considered a safe drug, it presents different adverse effects, among them the most common is the considerable increase in body weight.
Objective: to identify the relationship between the use of valproic acid in patients with antiepileptic treatment and weight gain.
Method: systematic review carried out at the Universidad Abierta Interamericana, Argentina, in which an exhaustive search of studies was carried out in the PubMed database with MeSH terms on Valproic acid AND weight gain. Once the articles were selected after applying the inclusion and exclusion criteria, 17 remained, which were useful to carry out this research.
Results: the information from the articles found reveals that the mechanisms through which valproic acid can generate this increase in body weight are still not fully clarified. Several hypotheses have been proposed; the most frequent in the literature are: hyperinsulinemia and insulin resistance, as well as hyperleptinemia and leptin resistance, among others. Patients who present weight gain have important health consequences, particularly the development of obesity and the association with dyslipidemia, arterial hypertension, type 2 diabetes mellitus, and atherosclerosis. In addition, by generating changes in body image, it can bring depression, decreased self-esteem and self-confidence, which causes non-compliance and abandonment of treatment.
Conclusion: the causal relationship of valproic acid on weight gain in patients with epilepsy is observed.
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References
1. Rauchenzauner M, Haberlandt E, Scholl-Bürgi S, Karall D, Schoenherr E, Tatarczyk T, et al. Effect of valproic acid treatment on body composition, leptin and the soluble leptin receptor in epileptic children. Epilepsy Res [Internet]. 2008 Aug [citado 25 Dic 2022]; 80(2-3):142-9. DOI: https://doi.org/10.1016/j.eplepsyres.2008.03.017
2. Demir E, Aysun S. Weight gain associated with valproate in childhood. Ped Neurol [Internet]. 2000 May [citado 25 Dic 2022]; 22(5):361-4. DOI: https://doi.org/10.1016/S0887-8994(00)00133-8
3. Perucca E. Pharmacological and Therapeutic Properties of Valproate: A Summary After 35 Years of Clinical Experience. CNS Drugs [Internet]. 2002 [citado 25 Dic 2022]; 16(10):695-714. Disponible en: https://link.springer.com/article/10.2165/00023210-200216100-00004
4. Löscher W. Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol [Internet]. 1999 Jun [citado 25 Dic 2022]; 58(1):31-59. DOI: https://doi.org/10.1016/S0301-0082(98)00075-6
5. Löscher W. Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. Neurochem Res [Internet]. 1993 Apr [citado 25 Dic 2022]; 18(4):485-502. Disponible en: https://link.springer.com/article/10.1007/BF00967253
6. Hamed SA. Leptin and insulin homeostasis in epilepsy: Relation to weight adverse conditions. Epilepsy Res [Internet]. 2007 Jun [citado 25 Dic 2022]; 75(1):1-9. DOI: https://doi.org/10.1016/j.eplepsyres.2007.04.001
7. Tokgoz H, Aydin K, Oran B, Kiyici A. Plasma leptin, neuropeptide Y, ghrelin, and adiponectin levels and carotid artery intima media thickness in epileptic children treated with valproate. Childs Nerv Syst [Internet]. 2012 Jul [citado 25 Dic 2022]; 28(7):1049-53. Disponible en: https://link.springer.com/article/10.1007/s00381-012-1788-7
8. Wirrell EC. Valproic acid-associated weight gain in older children and teens with epilepsy. Ped Neurol [Internet]. 2003 Feb [citado 25 Dic 2022]; 28(2):126-9. DOI: https://doi.org/10.1016/S0887-8994(02)00505-2
9. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. BMJ [Internet]. 1981 Aug [citado 25 Dic 2022]; 283(6291):577-81. DOI: https://doi.org/10.1136/bmj.283.6291.577
10. Dinesen H, Gram L, Andersen T, Dam M. Weight gain during treatment with valproate. Acta Neurol Scand [Internet]. 1984 Jan [citado 25 Dic 2022]; 70(2):65-69. DOI: https://doi.org/10.1111/j.1600-0404.1984.tb00804.x
11. Hamed SA, Fida NM, Hamed EA. States of serum leptin and insulin in children with epilepsy: Risk predictors of weight gain. Eur J Paed Neurol [Internet]. 2009 May [citado 25 Dic 2022]; 13(3):261-8. DOI: https://doi.org/10.1016/j.ejpn.2008.05.005
12. Verrotti A, la Torre R, Trotta D, Mohn A, Chiarelli F. Valproate-Induced Insulin Resistance and Obesity in Children. Horm Res Paed [Internet]. 2009 [citado 25 Dic 2022]; 71(3):125-31. DOI: https://doi.org/10.1159/000197868
13. Sharpe C, Wolfson T, Trauner DA. Weight Gain in Children Treated With Valproate. J Child Neurol [Internet]. 2009 Mar [citado 25 Dic 2022]; 24(3):338-41. DOI: https://doi.org/10.1177/0883073808323023
14. Petty SJ, Kantor S, Lawrence KM, Berkovic SF, Collins M, Hill KD, et al. Weight and fat distribution in patients taking valproate: A valproate-discordant gender-matched twin and sibling pair study. Epilepsia [Internet]. 2014 Oct [citado 25 Dic 2022]; 55(10):1551-7. DOI: https://doi.org/10.1111/epi.12745
15. El-Khatib F, Rauchenzauner M, Lechleitner M, Hoppichler F, Naser A, Waldmann M, et al. Valproate, weight gain and carbohydrate craving: A gender study. Seizure. 2007 Apr [citado 25 Dic 2022]; 16(3):226-32. DOI: https://doi.org/10.1016/j.seizure.2006.12.009
16. Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PS. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology [Internet]. 2001 Jan [citado 25 Dic 2022]; 56(2):172-7. DOI: https://doi.org/10.1212/WNL.56.2.172
17. Pylvänen V, Pakarinen A, Knip M, Isojärvi J. Insulin-related metabolic changes during treatment with valproate in patients with epilepsy. Epilepsy Behav [Internet]. 2006 May [citado 25 Dic 2022]; 8(3):643-8. DOI: https://doi.org/10.1016/j.yebeh.2006.02.008
18. Isojärvi JIT, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KTS, Myllyla VV. Obesity and endocrine disorders in women taking valproate for epilepsy: Valproate and Endocrine Disorders. Ann Neurol [Internet]. 1996 May [citado 25 Dic 2022]; 39(5):579-84. DOI: https://doi.org/10.1002/ana.410390506
19. Meral C, Cekmez F, Vurucu S, Tascılar E, Pirgon O, Canpolat FE, et al. New adipocytokines (vaspin, apelin, visfatin, adiponectin) levels in children treated with valproic acid. Eur Cytokine Netw [Internet]. 2011 Jun [citado 25 Dic 2022]; 22(2):118-22. DOI: https://doi.org/10.1684/ecn.2011.0284
20. Greco R, Latini G, Chiarelli F, Iannetti P, Verrotti A. Leptin, ghrelin, and adiponectin in epileptic patients treated with valproic acid. Neurology [Internet]. 2005 Dec [citado 25 Dic 2022]; 65(11):1808-9. DOI: https://doi.org/10.1212/01.wnl.0000187074.27586.d1
21. Gungor S, Yücel G, Akinci A, Tabel Y, Ozerol IH, Yologlu S. The Role of Ghrelin in Weight Gain and Growth in Epileptic Children Using Valproate. J Child Neurol [Internet]. 2007 Dec [citado 25 Dic 2022]; 22(12):1384-8. DOI: https://doi.org/10.1177/0883073807307096
22. Wong HY, Chu TS, Lai JC, Fung KP, Fok TF, Fujii T, et al. Sodium valproate inhibits glucose transport and exacerbates Glut1-deficiency in vitro. J Cell Biochem [Internet]. 2005 Nov [citado 25 Dic 2022]; 96(4):775-85. DOI: https://doi.org/10.1002/jcb.20555
23. Luef G, Abraham I, Haslinger M, Trinka E, Seppi K, Unterberger I, et al. Polycystic ovaries, obesity and insulin resistance in women with epilepsy. J Neurol [Internet]. 2002 Jul [citado 25 Dic 2022]; 249(7):835-41. Disponible en: https://link.springer.com/article/10.1007/s00415-002-0731-3
24. Luef G, Abraham I, Hoppichler F, Trinka E, Unterberger I, Bauer G, et al. Increase in postprandial serum insulin levels in epileptic patients with valproic acid therapy. Metabolism [Internet]. 2002 Oct [citado 25 Dic 2022]; 51(10):1274-8. DOI: https://doi.org/10.1053/meta.2002.34708
25. Morrell MJ, Isojärvi J, Taylor AE, Dam M, Ayala R, Gomez G, et al. Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy. Epilepsy Res [Internet]. 2003 May [citado 25 Dic 2022]; 54(2-3):189-99. DOI: https://doi.org/10.1016/S0920-1211(03)00085-8
26. Verrotti A, Greco R, Latini G, De Simone M, Chiarelli F. Obesity and Plasma Concentrations of Alpha-Tocopherol and Beta-Carotene in Epileptic Girls Treated with Valproate. Neuroendocrinol [Internet]. 2004 [citado 25 Dic 2022]; 79(3):157-62. DOI: https://doi.org/10.1159/000077274
27. Aydin K, Serdaroglu A, Okuyaz C, Bideci A, Gucuyener K. Serum Insulin, Leptin, and Neuropeptide Y Levels in Epileptic Children Treated With Valproate. J Child Neurol [Internet]. 2005 Oct [citado 25 Dic 2022]; 20(10):848-51. Disponible en: https://pubmed.ncbi.nlm.nih.gov/16417885/
28. Pylvänen V, Pakarinen A, Knip M, Isojärvi J. Characterization of Insulin Secretion in Valproate-treated Patients with Epilepsy. Epilepsia [iInternet]. 2006 Sep [citado 25 Dic 2022]; 47(9):1460-4. DOI: https://doi.org/10.1111/j.1528-1167.2006.00546.x
29. Rauchenzauner M, Haberlandt E, Scholl-Bürgi S, Ernst B, Hoppichler F, Karall D, et al. Adiponectin and visfatin concentrations in children treated with valproic acid. Epilepsia [Internet]. 2008 Feb [citado 25 Dic 2022]; 49(2):353-7. DOI: https://doi.org/10.1111/j.1528-1167.2007.01460.x
30. Grosso S, Mostardini R, Piccini B, Balestri P. Body Mass Index and Serum Lipid Changes During Treatment with Valproic Acid in Children with Epilepsy. Ann Pharmacother [Internet]. 2009 Jan [citado 25 Dic 2022]; 43(1):45-50. DOI: https://doi.org/10.1345/aph.1l414
31. Cansu A, Serdaroglu A, Çamurdan O, Hırfanoğlu T, Cinaz P. Serum Insulin, Cortisol, Leptin, Neuropeptide Y, Galanin and Ghrelin Levels in Epileptic Children Receiving Valproate. Horm Res Paed [Internet]. 2011 [citado 25 Dic 2022]; 76(1):65-71. DOI: https://doi.org/10.1159/000327367
2. Demir E, Aysun S. Weight gain associated with valproate in childhood. Ped Neurol [Internet]. 2000 May [citado 25 Dic 2022]; 22(5):361-4. DOI: https://doi.org/10.1016/S0887-8994(00)00133-8
3. Perucca E. Pharmacological and Therapeutic Properties of Valproate: A Summary After 35 Years of Clinical Experience. CNS Drugs [Internet]. 2002 [citado 25 Dic 2022]; 16(10):695-714. Disponible en: https://link.springer.com/article/10.2165/00023210-200216100-00004
4. Löscher W. Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol [Internet]. 1999 Jun [citado 25 Dic 2022]; 58(1):31-59. DOI: https://doi.org/10.1016/S0301-0082(98)00075-6
5. Löscher W. Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. Neurochem Res [Internet]. 1993 Apr [citado 25 Dic 2022]; 18(4):485-502. Disponible en: https://link.springer.com/article/10.1007/BF00967253
6. Hamed SA. Leptin and insulin homeostasis in epilepsy: Relation to weight adverse conditions. Epilepsy Res [Internet]. 2007 Jun [citado 25 Dic 2022]; 75(1):1-9. DOI: https://doi.org/10.1016/j.eplepsyres.2007.04.001
7. Tokgoz H, Aydin K, Oran B, Kiyici A. Plasma leptin, neuropeptide Y, ghrelin, and adiponectin levels and carotid artery intima media thickness in epileptic children treated with valproate. Childs Nerv Syst [Internet]. 2012 Jul [citado 25 Dic 2022]; 28(7):1049-53. Disponible en: https://link.springer.com/article/10.1007/s00381-012-1788-7
8. Wirrell EC. Valproic acid-associated weight gain in older children and teens with epilepsy. Ped Neurol [Internet]. 2003 Feb [citado 25 Dic 2022]; 28(2):126-9. DOI: https://doi.org/10.1016/S0887-8994(02)00505-2
9. Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. BMJ [Internet]. 1981 Aug [citado 25 Dic 2022]; 283(6291):577-81. DOI: https://doi.org/10.1136/bmj.283.6291.577
10. Dinesen H, Gram L, Andersen T, Dam M. Weight gain during treatment with valproate. Acta Neurol Scand [Internet]. 1984 Jan [citado 25 Dic 2022]; 70(2):65-69. DOI: https://doi.org/10.1111/j.1600-0404.1984.tb00804.x
11. Hamed SA, Fida NM, Hamed EA. States of serum leptin and insulin in children with epilepsy: Risk predictors of weight gain. Eur J Paed Neurol [Internet]. 2009 May [citado 25 Dic 2022]; 13(3):261-8. DOI: https://doi.org/10.1016/j.ejpn.2008.05.005
12. Verrotti A, la Torre R, Trotta D, Mohn A, Chiarelli F. Valproate-Induced Insulin Resistance and Obesity in Children. Horm Res Paed [Internet]. 2009 [citado 25 Dic 2022]; 71(3):125-31. DOI: https://doi.org/10.1159/000197868
13. Sharpe C, Wolfson T, Trauner DA. Weight Gain in Children Treated With Valproate. J Child Neurol [Internet]. 2009 Mar [citado 25 Dic 2022]; 24(3):338-41. DOI: https://doi.org/10.1177/0883073808323023
14. Petty SJ, Kantor S, Lawrence KM, Berkovic SF, Collins M, Hill KD, et al. Weight and fat distribution in patients taking valproate: A valproate-discordant gender-matched twin and sibling pair study. Epilepsia [Internet]. 2014 Oct [citado 25 Dic 2022]; 55(10):1551-7. DOI: https://doi.org/10.1111/epi.12745
15. El-Khatib F, Rauchenzauner M, Lechleitner M, Hoppichler F, Naser A, Waldmann M, et al. Valproate, weight gain and carbohydrate craving: A gender study. Seizure. 2007 Apr [citado 25 Dic 2022]; 16(3):226-32. DOI: https://doi.org/10.1016/j.seizure.2006.12.009
16. Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PS. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology [Internet]. 2001 Jan [citado 25 Dic 2022]; 56(2):172-7. DOI: https://doi.org/10.1212/WNL.56.2.172
17. Pylvänen V, Pakarinen A, Knip M, Isojärvi J. Insulin-related metabolic changes during treatment with valproate in patients with epilepsy. Epilepsy Behav [Internet]. 2006 May [citado 25 Dic 2022]; 8(3):643-8. DOI: https://doi.org/10.1016/j.yebeh.2006.02.008
18. Isojärvi JIT, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KTS, Myllyla VV. Obesity and endocrine disorders in women taking valproate for epilepsy: Valproate and Endocrine Disorders. Ann Neurol [Internet]. 1996 May [citado 25 Dic 2022]; 39(5):579-84. DOI: https://doi.org/10.1002/ana.410390506
19. Meral C, Cekmez F, Vurucu S, Tascılar E, Pirgon O, Canpolat FE, et al. New adipocytokines (vaspin, apelin, visfatin, adiponectin) levels in children treated with valproic acid. Eur Cytokine Netw [Internet]. 2011 Jun [citado 25 Dic 2022]; 22(2):118-22. DOI: https://doi.org/10.1684/ecn.2011.0284
20. Greco R, Latini G, Chiarelli F, Iannetti P, Verrotti A. Leptin, ghrelin, and adiponectin in epileptic patients treated with valproic acid. Neurology [Internet]. 2005 Dec [citado 25 Dic 2022]; 65(11):1808-9. DOI: https://doi.org/10.1212/01.wnl.0000187074.27586.d1
21. Gungor S, Yücel G, Akinci A, Tabel Y, Ozerol IH, Yologlu S. The Role of Ghrelin in Weight Gain and Growth in Epileptic Children Using Valproate. J Child Neurol [Internet]. 2007 Dec [citado 25 Dic 2022]; 22(12):1384-8. DOI: https://doi.org/10.1177/0883073807307096
22. Wong HY, Chu TS, Lai JC, Fung KP, Fok TF, Fujii T, et al. Sodium valproate inhibits glucose transport and exacerbates Glut1-deficiency in vitro. J Cell Biochem [Internet]. 2005 Nov [citado 25 Dic 2022]; 96(4):775-85. DOI: https://doi.org/10.1002/jcb.20555
23. Luef G, Abraham I, Haslinger M, Trinka E, Seppi K, Unterberger I, et al. Polycystic ovaries, obesity and insulin resistance in women with epilepsy. J Neurol [Internet]. 2002 Jul [citado 25 Dic 2022]; 249(7):835-41. Disponible en: https://link.springer.com/article/10.1007/s00415-002-0731-3
24. Luef G, Abraham I, Hoppichler F, Trinka E, Unterberger I, Bauer G, et al. Increase in postprandial serum insulin levels in epileptic patients with valproic acid therapy. Metabolism [Internet]. 2002 Oct [citado 25 Dic 2022]; 51(10):1274-8. DOI: https://doi.org/10.1053/meta.2002.34708
25. Morrell MJ, Isojärvi J, Taylor AE, Dam M, Ayala R, Gomez G, et al. Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy. Epilepsy Res [Internet]. 2003 May [citado 25 Dic 2022]; 54(2-3):189-99. DOI: https://doi.org/10.1016/S0920-1211(03)00085-8
26. Verrotti A, Greco R, Latini G, De Simone M, Chiarelli F. Obesity and Plasma Concentrations of Alpha-Tocopherol and Beta-Carotene in Epileptic Girls Treated with Valproate. Neuroendocrinol [Internet]. 2004 [citado 25 Dic 2022]; 79(3):157-62. DOI: https://doi.org/10.1159/000077274
27. Aydin K, Serdaroglu A, Okuyaz C, Bideci A, Gucuyener K. Serum Insulin, Leptin, and Neuropeptide Y Levels in Epileptic Children Treated With Valproate. J Child Neurol [Internet]. 2005 Oct [citado 25 Dic 2022]; 20(10):848-51. Disponible en: https://pubmed.ncbi.nlm.nih.gov/16417885/
28. Pylvänen V, Pakarinen A, Knip M, Isojärvi J. Characterization of Insulin Secretion in Valproate-treated Patients with Epilepsy. Epilepsia [iInternet]. 2006 Sep [citado 25 Dic 2022]; 47(9):1460-4. DOI: https://doi.org/10.1111/j.1528-1167.2006.00546.x
29. Rauchenzauner M, Haberlandt E, Scholl-Bürgi S, Ernst B, Hoppichler F, Karall D, et al. Adiponectin and visfatin concentrations in children treated with valproic acid. Epilepsia [Internet]. 2008 Feb [citado 25 Dic 2022]; 49(2):353-7. DOI: https://doi.org/10.1111/j.1528-1167.2007.01460.x
30. Grosso S, Mostardini R, Piccini B, Balestri P. Body Mass Index and Serum Lipid Changes During Treatment with Valproic Acid in Children with Epilepsy. Ann Pharmacother [Internet]. 2009 Jan [citado 25 Dic 2022]; 43(1):45-50. DOI: https://doi.org/10.1345/aph.1l414
31. Cansu A, Serdaroglu A, Çamurdan O, Hırfanoğlu T, Cinaz P. Serum Insulin, Cortisol, Leptin, Neuropeptide Y, Galanin and Ghrelin Levels in Epileptic Children Receiving Valproate. Horm Res Paed [Internet]. 2011 [citado 25 Dic 2022]; 76(1):65-71. DOI: https://doi.org/10.1159/000327367
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Published
2023-04-19
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1.
Torlasco MB, Estrin MA. Valproic acid and weight gain in patients receiving antiepileptic treatment: a systematic review. Rev Inf Cient [Internet]. 2023 Apr. 19 [cited 2025 Apr. 4];102:4197. Available from: https://revinfcientifica.sld.cu/index.php/ric/article/view/4197
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