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No. 2 (2025)

PSYCHOPHARMACOTHERAPY

Lamotrigine and Folic Acid in Bipolar Disorder — An Incompatible Combination? Clinical Cases

https://doi.org/10.48612/psyph/khh7-grev-1zr9

Published 2025-06-30

  • T.V. Zhilyaeva
    • ,
  • T.V. Bogdanova

T.V. Zhilyaeva
Privolzhsky Research Medical University; V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology

T.V. Bogdanova
Privolzhsky Research Medical University

Abstract

Lamotrigine is an anticonvulsant widely used in the treatment of various forms of epilepsy, as well as in the management of psychiatric disorders, particularly bipolar disorder, where it serves as a first-line treatment for bipolar depression and for maintenance therapy. It is well established that antiepileptic drugs, including lamotrigine, can interfere with folate metabolism. As a result, supplementation with folates — most commonly folic acid — is frequently recommended alongside their use. In 2016, an article published in *The Lancet Psychiatry* reported findings from a double-blind, randomized trial evaluating lamotrigine in bipolar depression. The authors concluded that “folic acid appears to nullify the effect of lamotrigine” (Geddes et al., 2016). However, as of May 2025, no further studies have been published to explore this interaction between folates and lamotrigine. Notably, there remains a lack of research assessing the potential interaction between lamotrigine and alternative forms of folate, such as methylfolate, which may have different pharmacological properties compared to folic acid. Moreover, the observed reduction in lamotrigine efficacy in the presence of folic acid was documented specifically in patients with bipolar depression. Therefore, it would be premature to extrapolate these findings to patients with other neurological or psychiatric conditions, as the mechanisms underlying lamotrigine’s effects may differ across disorders. The two clinical cases presented in this article highlight the importance of further investigation into the potential adverse interactions between lamotrigine and folic acid, and underscore the need for more nuanced clinical guidelines regarding folate supplementation in patients receiving lamotrigine therapy.

Keywords

lamotrigine, folic acid, methylfolate, bipolar affective disorder

PDF (Русский)

References

  1. Петрова Н.Н. Диагностика и терапия биполярного расстройства // Современная терапия психических расстройств. – 2024. – № 2. – С. 41–51. – https://doi.org/10.21265/PSYPH.2024.31.31.005
  2. Быков Ю.В., Беккер Р.А. Ламотриджин в качестве корректора ряда поведенческих нарушений при различных психических патологиях // Психиатрия и психофармакотерапия. – 2019. – Т. 21, № 3. – С. 39–51.
  3. Medford N., Sierra M., Baker D., David A.S. Understanding and treating depersonalisation disorder // Advances in Psychiatric Treatment. – 2005. – Vol. 11 (2). – Pр. 92–100. – https://doi.org/10.1192/apt.11.2.92
  4. Sierra M., Baker D., Medford N. et al. Lamotrigine as an add-on treatment for depersonalization disorder: a retrospective study of 32 cases // Clinical Neuropharmacology. – 2006. – Vol. 29 (5). – Pр. 253–258. – https://doi.org/10.1097/01.WNF.0000228368.17970.DA
  5. Erfurth A., Walden J., Grunze H. Lamotrigine in the treatment of schizoaffective disorder // Neuropsychobiology. – 1998. – Vol. 38 (3). – Pр. 204–205. – https://doi.org/10.1159/000026540
  6. Lieb K., Völlm B., Rücker G. et al. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials // The British Journal of Psychiatry. – 2010. – Vol. 196 (1). – Pр. 4–12. – https://doi.org/10.1192/bjp.bp.108.062984
  7. Hermle L., Simon M., Ruchsow M., Geppert M. Hallucinogen-persisting perception disorder // Therapeutic Advances in Psychopharmacology. – 2012. – Vol. 2 (5). – Pр. 199–205. – https://doi.org/10.1177/2045125312451270
  8. Hussain A., Dar M.A., Wani R.A. et al. Role of lamotrigine augmentation in treatment-resistant obsessive compulsive disorder: a retrospective case review from South Asia // Indian Journal of Psychological Medicine. – 2015. – Vol. 37 (2). – Pр. 154–158. – https://doi.org/10.4103/0253-7176.155613
  9. Naguy A., Al-Enezi N. Lamotrigine uses in psychiatric practice // American Journal of Therapeutics. – 2019. – Vol. 26 (1). – Рр. e96–e102. – https://doi.org/10.1097/MJT.0000000000000535
  10. Backonja M. Neuromodulating drugs for the symptomatic treatment of neuropathic pain // Current Pain and Headache Reports. – 2004. – Vol. 8. – Pр. 212–216. – https://doi.org/10.1007/s11916-004-0054-4
  11. Jensen T.S. Anticonvulsants in neuropathic pain: rationale and clinical evidence // European Journal of Pain. – 2002. – Vol. 6. – Рр. 61–68. – https://doi.org/10.1053/eujp.2001.0324
  12. Pappagallo M. Newer antiepileptic drugs: Possible uses in the treatment of neuropathic pain and migraine // Clinical Therapeutics. – 2003. – Vol. 25 (10). – Pp. 2506–2538. – https://doi.org/10.1016/s0149-2918(03)80314-4
  13. Delvendahl I. et al. Effects of lamotrigine on human motor córtex plasticity // Clinical Neurophysiology. – 2013. – Vol. 124 (1). – Pp. 148–153. – https://doi.org/10.1016/j.clinph.2012.05.011
  14. Eren İ., Nazıroğlu M., Demirdaş A. Protective effects of lamotrigine, aripiprazole and escitalopram on depression-induced oxidative stress in rat brain // Neurochemical Research. – 2007. – Vol. 32. – Pp. 1188–1195. – https://doi.org/10.1007/s11064-007-9289-x
  15. Geddes J.R. et al. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): A 2×2 factorial randomised trial // The Lancet Psychiatry. – 2016. – Vol. 3 (1). – Pp. 31–39. – https://doi.org/10.1016/S2215-0366(15)00450-2
  16. Huang H.L. et al. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients // Biomedical Reports. – 2016. – Vol. 32 (4). – Pp. 413–416. – https://doi.org/10.3892/br.2016.737
  17. Mischoulon D. et al. Does folic acid interfere with lamotrigine? // The Lancet Psychiatry. – 2016. – Vol. 3 (8). – Pp. 704–705. – https://doi.org/10.1016/S2215-0366(16)30167-5
  18. Абаимов Д.А. и др. Терапевтический лекарственный мониторинг ламотриджина: разработка фармакокинетических подходов с целью индивидуализации противосудорожной фармакотерапии // Эпилепсия и пароксизмальные состояния. – 2013. – Т. 5, № 4. – С. 44–48.
  19. Дмитренко Д.В. Профилактика врожденных пороков развития у плода с учетом фармакогенетических особенностей метаболизма антиэпилептических препаратов и наследственных нарушений фолатного цикла // Неврология, нейропсихиатрия, психосоматика. – 2014. – Т. S1. – С. 31–38.
  20. Steinweg D.L., Bentley M.L. Seizures following reduction in phenytoin level after orally administered folic acid // Neurology. – 2005. – Vol. 64 (11). – Art. 1982. – https://doi.org/10.1212/01.WNL.0000163997.67472.C5
  21. Seligmann H. et al. Phenytoin-folic acid interaction: A lesson to be learned // Clinical Neuropharmacology. – 1999. – Vol. 22 (5). – Pp. 268–272.
  22. Berg, M.J. et al. Phenytoin pharmacokinetics: Before and after folic acid administration // Epilepsia. – 1992. – Vol. 33 (4). – Pp. 712–720. – https://doi.org/10.1111/j.1528-1157.1992.tb02352.x
  23. Umur A.S. et al. Simultaneous folate intake may prevent advers effect of valproic acid on neurulating nervous system // Child’s Nervous System. – 2012. – Vol. 28. – Pp. 729–737. – https://doi.org/10.1007/s00381-011-1673-9
  24. Lam N.S.K. et al. The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review // Biomedicine & Pharmacotherapy. – 2022. – Vol. 146. – Art. 112541. – https://doi.org/10.1016/j.biopha.2021.112541
  25. Crider K.S., Bailey L.B., Berry R.J. Folic acid food fortification — its history, effect, concerns, and future directions // Nutrients. – 2011. – Vol. 3 (3). – Pp. 370–384. – https://doi.org/10.3390/nu3030370
  26. Besag, F.M.C. et al. Efficacy and safety of lamotrigine in the treatment of bipolar disorder across the lifespan: A systematic review // Therapeutic Advances in Psychopharmacology. – 2021. – Vol. 11. – Art. 20451253211045870. – https://doi.org/10.1177/20451253211045870
  27. Tunbridge E.M. et al. Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: analysis of the CEQUEL clinical trial // BipolarDisorders. – 2017. – Vol. 19 (6). – Pp. 477–486. – https://doi.org/10.1111/bdi.12531
  28. Ушкалова А.В., Ушкалова Е.А., Шифман Е.М., Мосолов С.Н. Фармакотерапия психических расстройств при беременности // Биологические методы терапии психических расстройств (доказательная медицина – клинической практике). – М.: Социально-политическая мысль, 2012. – С. 913–982.
  29. Nucera B. et al. Treatment and care of women with epilepsy before, during, and after pregnancy: A practical guide // Therapeutic Advances in Neurological Disorders. – 2022. – Vol. 15. – Art. 17562864221101687. – https://doi.org/10.1177/17562864221101687
  30. Harden C.L. et al. Management issues for women with epilepsy — Focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society // Epilepsia. – 2009. – Vol. 50 (5). – Pp. 1247–1255. – https://doi.org/10.1111/j.1528-1167.2009.02130.x
  31. Müffelmann B. et al. Frauen mit Epilepsie: Wie erfolgt die Beratung bei Kinderwunsch und in der Schwangerschaft? — Eine Fallserie aus einer spezialisierten Epilepsieambulanz [Women with epilepsy before and during pregnancy: a case series of outpatient counseling in a tertiary epilepsy center] // Der Nervenarzt. – 2022. – Vol. 93 (6). – Pp. 566–574. – https://doi.org/10.1007/s00115-021-01198-7
  32. Goo Y. et al. Dose monitoring of lamotrigine monotherapy in pregnancy: Are pregnant women with epilepsy currently optimally managed? A systematic review // Therapeutic Drug Monitoring. – 2024. – Vol. 46 (2). – Pp. 181–194. – https://doi.org/10.1097/FTD.0000000000001186
  33. Sarris J. et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce // The World Journal of Biological Psychiatry. – 2022. – Vol. 23 (6). – Pp. 424–455. – https://doi.org/10.1080/15622975.2021.2013041
  34. Maruf A. et al. Systematic review and meta-analysis of L-Methylfolate augmentation in depressive disorders // Pharmacopsychiatry. – 2022. – Vol. 55 (03). – Pp. 139–147. – https://doi.org/10.1055/a-1681-2047

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