Abstract
Objective: This study aims to characterize the rate of successful rechallenge considering the risk of recurrence of cutaneous adverse reactions with reintroduction of lamotrigine, as well as how to characterize cutaneous reactions appropriately, and important considerations in deciding whether to attempt reintroduction of lamotrigine.
Data Sources: A systematic review was conducted of PubMed, SCOPUS, and Web of Science databases. Search terms included lamotrigine, rash, and rechallenge or reintroduction.
Study Selection: The resulting articles (59) were imported into Covidence. After screening and application of inclusion/exclusion criteria, 11 articles were included.
Data Extraction and Synthesis: Variables extracted included study design, age of patient, lamotrigine dosing regimen, concomitant valproate use, use of other concomitant enzyme-inducing antiepileptic drugs, rash timing after starting lamotrigine, rash description, rash diagnosis, dermatologist evaluation, skin biopsy, hospitalization, time from initial rash onset until rechallenge, rechallenge lamotrigine dosing regimen, and response.
Results: There were 106 cases of rechallenge of lamotrigine. Over half (57%) of patients were female, and the average age was 35 years. Time from discontinuation of lamotrigine until rechallenge ranged from 1 week to 26 months, and there were 12 cases that continued lamotrigine without interruption or by reducing the dose. Patients who were rechallenged with lamotrigine successfully typically started the rechallenge with either 5 mg or 12.5 mg daily with a gradual upward titration until reaching desired dose. Successful rechallenge occurred in 84% of cases; reasons for unsuccessful rechallenge included severe or intolerable rash or other symptoms. Only 3 out of 106 cases had a dermatologist confirm the initial rash diagnosis.
Conclusions: Lamotrigine has been rechallenged safely in select cases; however, it is critical to confirm that the initial rash did not have specific features of a severe rash in order to proceed with safe reintroduction of lamotrigine. This article analyzes the cases in the literature to date and gives recommendations for how to assess whether to rechallenge lamotrigine.
J Clin Psychiatry 2026;87(1):25r15987
Author affiliations are listed at the end of this article.
Members Only Content
This full article is available exclusively to Professional tier members. Subscribe now to unlock the HTML version and gain unlimited access to our entire library plus all PDFs. If you’re already a subscriber, please log in below to continue reading.
References (37)
- Betchel NT, Fariba KA, Saadabadi A. Lamotrigine. StatPearls. StatPearls Publishing LLC.; 2024.
- Guvenir H, Arikoglu T, Vezir E, et al. Clinical phenotypes of severe cutaneous drug hypersensitivity reactions. Curr Pharm Des. 2019;25(36):3840–3854. PubMed CrossRef
- Wang C, Fan Z, He Y, et al. Analysis of the clinical characteristics of lamotrigine-induced haemophagocytic lymphohistiocytosis. J Clin Pharm Ther. 2022;47(6):745–751. PubMed CrossRef
- Wang H, Peng J, Zeng W, et al. Lamotrigine-induced hemophagocytic lymphohistiocytosis with DRESS. Clin Lab. 2024;70(2).
- Hopkins Z, Frigerio A, Clarke JT. Acute localized exanthematous pustulosis (ALEP) caused by lamotrigine. JAAD Case Rep. 2018;4(7):645–647. PubMed CrossRef
- Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60(4):392–400. PubMed CrossRef
- Calabrese JR, Bowden CL, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64(9):1013–1024. PubMed CrossRef
- Matsuo F, Gay P, Madsen J, et al. Lamotrigine high-dose tolerability and safety in patients with epilepsy: a double-blind, placebo-controlled, eleven-week study. Epilepsia. 1996;37(9):857–862. PubMed CrossRef
- Mackay FJ, Wilton LV, Pearce GL, et al. Safety of long-term lamotrigine in epilepsy. Epilepsia. 1997;38(8):881–886. PubMed CrossRef
- Seo H, Chiesa A, Lee S, et al. Safety and tolerability of lamotrigine: results from 12 placebo-controlled clinical trials and clinical implications. Clin Neuropharmacol. 2011;34(1):39–47. PubMed CrossRef
- Manasco P. Skin rash associated with Lamictal: incidence, time to onset and risk factors.
- Woo YS, Bahk WM, Jon DI, et al. Rash in adult patients receiving lamotrigine to treat bipolar I disorder in Korea: a multicenter, prospective, naturalistic, open-label trial. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(7):1147–1152. PubMed CrossRef
- Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia. 1999;40(7):985–991. PubMed CrossRef
- Kanner AM, Frey M. Adding valproate to lamotrigine: a study of their pharmacokinetic interaction. Neurology. 2000;55(4):588–591. PubMed CrossRef
- P-Codrea S, Sidenius P, Dam M. Lamotrigine-induced rash - worth a rechallenge. Acta Neurol Scand. 2005;111(3):191–194. PubMed
- Naisbitt DJ, Williams DP, Pirmohamed M, et al. Reactive metabolites and their role in drug reactions. Curr Opin Allergy Clin Immunol. 2001;1(4):317–325. PubMed CrossRef
- Gaeta F, Alonzi C, Valluzzi RL, et al. Hypersensitivity to lamotrigine and nonaromatic anticonvulsant drugs: a review. Curr Pharm Des. 2008;14(27):2874–2882. PubMed CrossRef
- Line J, Saville E, Meng X, et al. Why drug exposure is frequently associated with T-cell mediated cutaneous hypersensitivity reactions. Front Toxicol. 2023;5:1268107. PubMed CrossRef
- Manson LEN, Nijenhuis M, Soree B, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs. Eur J Hum Genet. 2024;32(8):903–911. PubMed CrossRef
- Shirzadi M, Saunes M, Reimers A, et al. Rash during lamotrigine treatment is not always drug hypersensitivity: a retrospective cohort study among children and adults. Seizure. 2021;89:12–18. PubMed CrossRef
- Houser J, Graham A. Rechallenge of lamotrigine after development of rash. Ment Health Clin. 2018;8(5):247–249. PubMed CrossRef
- Inaba T, Sogawa R, Mizoguchi Y, et al. Lamotrigine Rechallenge in Treatment-Resistant Bipolar Disorder. Prim Care Companion. CNS Disord. 2018;20(2):17m02231. PubMed CrossRef
- Serrani Azcurra DJ. Lamotrigine rechallenge after a skin rash. A combined study of open cases and a meta-analysis. Rev Psiquiatr Salud Ment. 2013;6(4):144–149. PubMed CrossRef
- Aiken CB, Orr C. Rechallenge with lamotrigine after a rash: a prospective case series and review of the literature. Psychiatry (Edgmont). 2010;7(5):27–32. PubMed
- Lukic S, Spasic M. Rechallenge of lamotrigine add-on therapy with valproate in patients with pharmacoresistant epilepsy and history of rash. EPILEPSIA. 2007;48:116–116.
- Manfredi G, Pacchiarotti I, Kotzalidis GD, et al. Successful rechallenge with slowly titrated lamotrigine after rash. Bipolar Disord. 2004;6(4):338–339. PubMed CrossRef
- Huang CW, Tsai JJ, Lai ML. Lamotrigine-related skin rashes in adults. Kaohsiung J Med Sci. 2002;18(11):566–572. PubMed
- Buzan RD, Dubovsky SL. Recurrence of lamotrigine-associated rash with rechallenge. J Clin Psychiatry. 1998;59(2):87. PubMed
- Tavernor SJ, Wong IC, Newton R, Brown SW. Rechallenge with lamotrigine after initial rash. Seizure. 1995;4(1):67–71. PubMed CrossRef
- Kaffenberger B, Korman A, Madigan L, et al. Morbilliform Eruptions. Dialogues in Dermatology Podcast Transcript; 2024.
- Santiago Mangual K, Rice S, Stoff B. Commentary: Morbilliform Eruptions. Dialogues In Dermatology Podcast Transcript; 2024.
- Lorberg B, Youssef NA, Bhagwagar Z. Lamotrigine-associated rash: to rechallenge or not to rechallenge? Int J Neuropsychopharmacol. 2009;12(2):257–265. PubMed CrossRef
- Lehloenya RJ, Phillips EJ, Pasieka HB, et al. Recognizing drug hypersensitivity in pigmented skin. Immunol Allergy Clin North Am. 2022;42(2):219–238. PubMed CrossRef
- Schaub N, Bircher A. Severe hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro. Allergy. 2000;55(2):191–193. PubMed CrossRef
- Elzagallaai AA, Knowles SR, Rieder MJ, et al. Patch testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review. Drug Saf. 2009;32(5):391–408. PubMed CrossRef
- Neuman MG, Cohen L, Nanau RM, et al. Genetic and immune predictors for hypersensitivity syndrome to antiepileptic drugs. Transl Res. 2012;159(5):397–406. PubMed CrossRef
- Fang H, Xu X, Kaur K, et al. A screening test for HLA-Bp15:02 in a large United States patient cohort identifies broader risk of carbamazepine-induced adverse events. Front Pharmacol. 2019;10:149. PubMed CrossRef
