View source for Lamotrigine

{{Short description|Medication used for bipolar disorder, epilepsy, & many seizure disorders}}
{{Use dmy dates|date=September 2025}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 420280917
| image = Lamotrigine.svg
| image_class = skin-invert-image
| width = 180px
| image2 = Lamotrigine ball-and-stick model.png
| image_class2 = 
| width2 = 180px
| imageL = 
| image_classL = 
| widthL = 
| altL = 
| imageR = 
| widthR = 
| altR = 
| caption = <!-- Clinical data -->
| pronounce = {{IPAc-en|l|ə|ˈ|m|oʊ|t|r|ᵻ|ˌ|dʒ|iː|n}} {{respell|lə|MOH|trih|jeen}}
| tradename = Lamictal, others<ref name=brands/>
| Drugs.com = {{drugs.com|monograph|lamotrigine}}
| MedlinePlus = a695007
| DailyMedID = Lamotrigine
| pregnancy_AU = D
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Lamotrigine Use During Pregnancy | website=Drugs.com | date=8 October 2019 | url=https://www.drugs.com/pregnancy/lamotrigine.html | access-date=24 March 2020 | archive-date=25 January 2021 | archive-url=https://web.archive.org/web/20210125224408/https://www.drugs.com/pregnancy/lamotrigine.html | url-status=live }}</ref>
| pregnancy_category = 
| routes_of_administration = [[Oral administration|Oral]] (by mouth)
| class = [[Phenyltriazine]]
| ATCvet = 
| ATC_prefix = N03
| ATC_suffix = AX09
| ATC_supplemental = <!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = 
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = Rx-only
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = <ref name="Lamictal FDA label" /><ref name="Lamictal XR FDA label">{{cite web | title=Lamictal XR- lamotrigine tablet, film coated, extended release Lamictal XR- lamotrigine kit | website=DailyMed | date=13 April 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e2c9a35-6a39-41d7-ad84-3c0bb8894b09 | access-date=27 August 2022 | archive-date=27 August 2022 | archive-url=https://web.archive.org/web/20220827011250/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e2c9a35-6a39-41d7-ad84-3c0bb8894b09 | url-status=live }}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Lamictal | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/referrals/lamictal | access-date=27 August 2022 | archive-date=27 August 2022 | archive-url=https://web.archive.org/web/20220827012357/https://www.ema.europa.eu/en/medicines/human/referrals/lamictal | url-status=live }}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->| bioavailability = 98%
| protein_bound = 55%
| metabolism = [[Liver]] (mostly [[UGT1A4]]-mediated)
| metabolites = 
| onset = 
| elimination_half-life = 29 hours
| duration_of_action = 
| excretion = [[Urine]] (65%), [[feces]] (2%)

<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 84057-84-1
| CAS_supplemental = 
| PubChem = 3878
| IUPHAR_ligand = 2622
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00555
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3741
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = U3H27498KS
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00354
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 6367
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 741
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = BW-430C; BW430C; 3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine

<!-- Chemical and physical data -->| IUPAC_name = 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine
| C = 9
| H = 7
| Cl = 2
| N = 5
| SMILES = NC1=NC(N)=NN=C1C2=CC=CC(Cl)=C2Cl
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H7Cl2N5/c10-5-3-1-2-4(6(5)11)7-8(12)14-9(13)16-15-7/h1-3H,(H4,12,13,14,16)
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PYZRQGJRPPTADH-UHFFFAOYSA-N
| density = 
| density_notes = 
| melting_point = 
| melting_high = 
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| boiling_point = 
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| sol_units = 
| specific_rotation = 
}}

<!-- Definition and medical uses -->
'''Lamotrigine''' ({{IPAc-en|l|ə|ˈ|m|oʊ|t|r|ᵻ|ˌ|dʒ|iː|n}} {{respell|luh|MOH|trih|jeen}}), sold under the brand name '''Lamictal''' among others, is a [[medication]] used to treat [[epilepsy]] and stabilize mood in [[bipolar disorder]].<ref name="Lamictal FDA label" /><ref name=AHFS2017>{{cite web|title=Lamotrigine|url=https://www.drugs.com/monograph/lamotrigine.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2017|archive-date=10 December 2017|archive-url=https://web.archive.org/web/20171210020403/https://www.drugs.com/monograph/lamotrigine.html|url-status=live}}</ref> For epilepsy, this includes [[focal seizure]]s, [[tonic-clonic seizure]]s, and seizures in [[Lennox-Gastaut syndrome]].<ref name=AHFS2017/> In bipolar disorder, lamotrigine has not been shown to reliably treat acute [[Depression (mood)|depression]] in any groups except for the severely depressed; but for patients with bipolar disorder who are not currently symptomatic, it appears to reduce the risk of future episodes of depression.<ref>{{cite web|title=Lamotrigine: Its Role in Bipolar Disorder|date=26 November 2019 |url=https://www.psychiatrictimes.com/view/lamotrigine-its-role-bipolar-disorder|publisher=PsychiatricTimes|access-date=1 September 2020|archive-date=26 January 2021|archive-url=https://web.archive.org/web/20210126155815/https://www.psychiatrictimes.com/view/lamotrigine-its-role-bipolar-disorder|url-status=live}}</ref> Lamotrigine is also used off label for unipolar depression ([[major depressive disorder]]) and [[depersonalization-derealization disorder]].<ref>{{cite journal | url=https://www.tandfonline.com/doi/full/10.1080/15299732.2023.2231920 | doi=10.1080/15299732.2023.2231920 | title=The Treatment of Depersonalization-Derealization Disorder: A Systematic Review | date=2024 | journal=Journal of Trauma & Dissociation | volume=25 | issue=1 | pages=6–29 | pmid=37431255 | vauthors = Wang S, Zheng S, Zhang FX, Ma R, Feng S, Song M, Zhu H, Jia H | url-access=subscription }}</ref>

<!-- Side effects and mechanism -->
Common side effects include [[nausea]], [[Somnolence|sleepiness]], [[headache]], [[vomiting]], [[Ataxia|trouble with coordination]], and [[rash]].<ref name=AHFS2017/> Serious side effects include [[hemolytic anemia|excessive breakdown of red blood cells]], increased risk of [[suicide]], severe skin reaction ([[Stevens–Johnson syndrome]]), and [[allergic reactions]], which can be fatal.<ref name=AHFS2017/> Lamotrigine is a [[phenyltriazine]],<ref name="Lamictal FDA label" /> making it chemically different from other [[anticonvulsant]]s.<ref name=AHFS2017/> Its mechanism of action is not clear, but it appears to inhibit release of excitatory neurotransmitters via [[voltage-sensitive sodium channels]] and [[voltage-gated calcium channel]]s in neurons.<ref name=AHFS2017/><ref>{{cite web| url= https://pubchem.ncbi.nlm.nih.gov/compound/3878#section=Top| title= Lamotrigine| website= PubChem Open Chemistry Database| publisher= National Institutes of Health| location= US| access-date= 13 December 2016| archive-date= 6 September 2016| archive-url= https://web.archive.org/web/20160906142844/http://pubchem.ncbi.nlm.nih.gov/compound/3878#section=Top| url-status= live}}</ref><ref>{{cite journal | vauthors = Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM | title = Lamotrigine: a review of its use in bipolar disorder | journal = Drugs | volume = 63 | issue = 19 | pages = 2029–2050 | date = 1 October 2003 | pmid = 12962521 | doi = 10.2165/00003495-200363190-00009 }}</ref>

<!-- History and culture -->
Lamotrigine was first marketed in Ireland in 1991,<ref name="pmid 18001843" /> and approved for use in the United States in 1994.<ref name=AHFS2017/><ref>{{cite book|vauthors=Shorvon SD, Perucca E, Engel J|title=The Treatment of Epilepsy|publisher=John Wiley & Sons, Incorporated|isbn=978-1-118-93699-3|page=1321|edition=4th|date=2015|url=https://books.google.com/books?id=ppKbCgAAQBAJ&pg=PT1535|access-date=31 August 2020|archive-date=2 August 2021|archive-url=https://web.archive.org/web/20210802114654/https://books.google.com/books?id=ppKbCgAAQBAJ&pg=PT1535|url-status=live}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> In 2023, it was the most commonly prescribed [[mood stabilizer]] and 59th most commonly prescribed medication in the United States, with more than 10{{nbsp}}million prescriptions.<ref>{{Cite web |title=The Top 300 of 2023 |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx |archive-date=12 August 2025 |access-date=13 August 2025 |website=clincalc.com}}</ref><ref>{{Cite web |title=Lamotrigine - Drug Usage Statistics, ClinCalc DrugStats Database |url=https://clincalc.com/DrugStats/Drugs/Lamotrigine |access-date=13 August 2025 |website=clincalc.com}}</ref>

==Medical uses==
===Epilepsy===
Lamotrigine is considered a first-line drug for primary generalized [[tonic-clonic seizures]] (includes simple partial, complex partial, and secondarily generalized seizures such as focal-onset tonic-clonic seizures). It is also used as an alternative or adjuvant medication for partial seizures, such as [[absence seizure]], [[myoclonic seizure]], and [[atonic seizures]].<ref>{{cite book | vauthors = Kasper D | veditors = Kasper D, Braunwald E, Fauci A, Hauser S, Longo D, Jameson J | title = Harrison's Principles of Internal Medicine | edition = 16th |publisher= McGraw-Hill|year=2005 |pages=3–22 |isbn= 978-0-07-146633-2|display-editors=etal}}</ref><ref>{{cite book |vauthors= Tierny LM |veditors= McPhee SJ, Papadakis MA |title= Current Medical Diagnosis and Treatment, 45th ed |publisher= McGraw-Hill |year= 2006 |isbn= 978-0-07-145410-0 |url-access= registration |url= https://archive.org/details/currentmedicaldi0000unse_q5e4 }}</ref> The evidence supporting the use of lamotrigine as an add-on therapy for drug-resistant generalized tonic-clonic seizures is not clear enough to inform clinical practice.<ref name="Bresnahan_2020" /> Although low-certainty evidence suggests that it reduces generalized tonic-clonic seizures by 50%, the level of uncertainty indicates that the actual findings could be significantly different.<ref name="Bresnahan_2020">{{cite journal | vauthors = Bresnahan R, Panebianco M, Marson AG | title = Lamotrigine add-on therapy for drug-resistant generalised tonic-clonic seizures | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 7 | article-number = CD007783 | date = July 2020 | pmid = 32609387 | pmc = 7387132 | doi = 10.1002/14651858.CD007783.pub3 }}</ref> Evidence supporting the use of lamotrigine as an add-on therapy for [[Management of drug-resistant epilepsy|drug-resistant focal epilepsy]] found that it is likely effective for reducing seizure frequency and is generally well tolerated.<ref name="Panebianco_2023">{{cite journal | vauthors = Panebianco M, Bresnahan R, Marson AG | title = Lamotrigine add-on therapy for drug-resistant focal epilepsy | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 12 | article-number = CD001909 | date = December 2023 | pmid = 38078494 | pmc = 10712213 | doi = 10.1002/14651858.CD001909.pub4 }}</ref> Lamotrigine has some side effects including a risk of dizziness, nausea, ataxia, or visual disturbances such as [[diplopia]].<ref name="Panebianco_2023" /> The long-term effects of lamotrigine have not been investigated.<ref name="Panebianco_2023" />

====Lennox–Gastaut syndrome====
Lamotrigine is one of a small number of FDA-approved therapies for the form of [[epilepsy]] known as [[Lennox–Gastaut syndrome]].<ref>{{cite journal | vauthors = Brigo F, Jones K, Eltze C, Matricardi S | title = Anti-seizure medications for Lennox-Gastaut syndrome | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | article-number = CD003277 | date = April 2021 | pmid = 33825230 | pmc = 8095011 | doi = 10.1002/14651858.CD003277.pub4 }}</ref> It reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks.<ref>{{cite journal | vauthors = French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE, Sachdeo RC, Beydoun A, Glauser TA | title = Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society | journal = Neurology | volume = 62 | issue = 8 | pages = 1261–1273 | date = April 2004 | pmid = 15111660 | doi = 10.1212/01.WNL.0000123695.22623.32 | doi-access = free }}</ref> Combination with [[valproate]] is common, but this increases the risk of [[Stevens–Johnson syndrome]], and necessitates reduced dosing due to the interaction of these drugs.<ref>{{cite journal | vauthors = Pellock JM | title = Managing pediatric epilepsy syndromes with new antiepileptic drugs | journal = Pediatrics | volume = 104 | issue = 5 Pt 1 | pages = 1106–1116 | date = November 1999 | pmid = 10545555 | doi = 10.1542/peds.104.5.1106 | s2cid = 1090325 }}</ref>

===Bipolar disorder===
Lamotrigine is approved in the US for maintenance treatment of [[bipolar I disorder]] and [[bipolar II disorder]].<ref>{{cite web |url=https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/pediatricadvisorycommittee/ucm235547.pdf |title=Lamictal (lamotrigine) Label Information |author=GlaxoSmithKline |website=[[Food and Drug Administration]] |date=12 October 2010 |access-date=5 August 2019 |archive-url=https://web.archive.org/web/20170420151835/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM235547.pdf |archive-date=20 April 2017 }}</ref> While the anticonvulsants [[carbamazepine]] and [[valproate]] are predominantly [[antimanic agent|antimanics]], lamotrigine has demonstrated efficacy only in preventing or reducing the risk of recurrent depressive episodes of bipolar disorder. The drug seems ineffective in the treatment of current rapid-cycling, acute mania, or acute depression in bipolar disorder.<ref name=PMC2580079>{{cite journal | vauthors = Nassir Ghaemi S, Shirzadi AA, Filkowski M | title = Publication bias and the pharmaceutical industry: the case of lamotrigine in bipolar disorder | journal = Medscape Journal of Medicine | volume = 10 | issue = 9 | page = 211 | year = 2008 | pmid = 19008973 | pmc = 2580079 }}</ref> Lamotrigine has been shown to be as effective as [[Lithium (medication)|lithium]], the standard treatment for bipolar disorder.<ref>{{cite journal | vauthors = Hashimoto Y, Kotake K, Watanabe N, Fujiwara T, Sakamoto S | title = Lamotrigine in the maintenance treatment of bipolar disorder | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 9 | article-number = CD013575 | date = September 2021 | pmid = 34523118 | pmc = 8440301 | doi = 10.1002/14651858.CD013575.pub2 }}</ref>

Lamotrigine has not demonstrated clear efficacy in treating acute mood episodes, either mania or depression. It has not demonstrated effectiveness in treating acute mania,<ref name="pmid12962521">{{cite journal | vauthors = Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM | title = Lamotrigine: a review of its use in bipolar disorder | journal = Drugs | volume = 63 | issue = 19 | pages = 2029–2050 | year = 2003 | pmid = 12962521 | doi = 10.2165/00003495-200363190-00009 }}</ref> and there is controversy regarding the drug's effectiveness in treating acute bipolar depression.<ref>{{cite journal | vauthors = Geddes JR, Miklowitz DJ | title = Treatment of bipolar disorder | journal = Lancet | volume = 381 | issue = 9878 | pages = 1672–1682 | date = May 2013 | pmid = 23663953 | pmc = 3876031 | doi = 10.1016/S0140-6736(13)60857-0 }}</ref> A paper written in 2008 by Nassir et al. reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines, and it concludes that lamotrigine has "very limited, if any, efficacy in the treatment of acute bipolar depression".<ref name=PMC2580079 /> A 2008 paper by Calabrese et al. examined much of the same data, and found that in five [[Placebo-controlled study|placebo-controlled studies]], lamotrigine did not significantly differ from placebo in the treatment of bipolar depression.<ref name="pmid18271912">{{cite journal | vauthors = Calabrese JR, Huffman RF, White RL, Edwards S, Thompson TR, Ascher JA, Monaghan ET, Leadbetter RA | title = Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials | journal = Bipolar Disorders | volume = 10 | issue = 2 | pages = 323–333 | date = March 2008 | pmid = 18271912 | doi = 10.1111/j.1399-5618.2007.00500.x }}</ref>  However, in a meta-analysis of these studies conducted in 2008, Geddes, Calabrese, and Goodwin found that lamotrigine was effective in individuals with bipolar depression, with a [[number needed to treat]] (NNT) of 11, or 7 in severe depression.<ref>{{cite journal | vauthors = Geddes JR, Calabrese JR, Goodwin GM | title = Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials | journal = The British Journal of Psychiatry | volume = 194 | issue = 1 | pages = 4–9 | date = January 2009 | pmid = 19118318 | doi = 10.1192/bjp.bp.107.048504 | doi-access = free }}</ref>

A 2013 review concluded that lamotrigine is recommended in bipolar maintenance when depression is prominent and that more research is needed regarding its role in the treatment of acute bipolar depression and unipolar depression. No information to recommend its use in other psychiatric disorders was found.<ref>{{cite journal | vauthors = Reid JG, Gitlin MJ, Altshuler LL | title = Lamotrigine in psychiatric disorders | journal = The Journal of Clinical Psychiatry | volume = 74 | issue = 7 | pages = 675–684 | date = July 2013 | pmid = 23945444 | doi = 10.4088/JCP.12r08046 }}</ref>

===Schizophrenia===
Lamotrigine, as a monotherapy, is not substantially effective against [[schizophrenia]]. However, various publications<ref>{{cite journal | vauthors = Tiihonen J, Wahlbeck K, Kiviniemi V | title = The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis | journal = Schizophrenia Research | volume = 109 | issue = 1–3 | pages = 10–14 | date = April 2009 | pmid = 19186030 | doi = 10.1016/j.schres.2009.01.002 | s2cid = 25302931 }}</ref><ref>{{cite journal | vauthors = Dursun SM, McIntosh D, Milliken H | title = Clozapine plus lamotrigine in treatment-resistant schizophrenia | journal = Archives of General Psychiatry | volume = 56 | issue = 10 | page = 950 | date = October 1999 | pmid = 10530638 | doi = 10.1001/archpsyc.56.10.950 }}</ref> and textbooks<ref>{{cite book | vauthors = Taylor DM |date= 2018  |title= The Maudsley Prescribing Guidelines in Psychiatry |publisher= Wiley | location = Hoboken, NJ |page= 159 |isbn= 978-1-119-44256-1}}</ref><ref>{{cite book | vauthors = Stahl SM |date= 2017 |title= Stahl's Essential Psychopharmacology Prescriber's Guide | edition = 6th |publisher = Cambridge University Press | location = Cambridge |page= 178 |isbn= 978-1-316-61813-4}}</ref> have expressed that lamotrigine could be added to [[clozapine]] as augmentation therapy against partial or non-responding patients with schizophrenia. Patients had statistically significant improvements in positive, negative and affective symptoms. Lamotrigine does not have a statistically significant effect with [[Antipsychotic|antipsychotics]] other than [[clozapine]], such as [[olanzapine]], [[risperidone]], [[haloperidol]], and [[zuclopenthixol]].<ref>{{cite journal | vauthors = Kremer I, Vass A, Gorelik I, Bar G, Blanaru M, Javitt DC, Heresco-Levy U | title = Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia | journal = Biological Psychiatry | volume = 56 | issue = 6 | pages = 441–446 | date = September 2004 | pmid = 15364042 | doi = 10.1016/j.biopsych.2004.06.029 | s2cid = 7479755 }}</ref>

===Other uses===
[[Off-label use]]s include the treatment of [[major depressive disorder]], [[peripheral neuropathy]], [[trigeminal neuralgia]], [[cluster headache]]s, [[migraine]]s, [[Visual snow syndrome|visual snow]], and reducing [[neuropathic pain]] from any cause,<ref>{{cite journal | vauthors = Backonja M | title = Neuromodulating drugs for the symptomatic treatment of neuropathic pain | journal = Current Pain and Headache Reports | volume = 8 | issue = 3 | pages = 212–216 | date = June 2004 | pmid = 15115640 | doi = 10.1007/s11916-004-0054-4 | s2cid = 24786792 }}</ref><ref>{{cite journal | vauthors = Jensen TS | title = Anticonvulsants in neuropathic pain: rationale and clinical evidence | journal = European Journal of Pain | volume = 6 Suppl A | issue = Suppl A | pages = 61–68 | year = 2002 | pmid = 11888243 | doi = 10.1053/eujp.2001.0324 | s2cid = 22742865 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pappagallo M | title = Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine | journal = Clinical Therapeutics | volume = 25 | issue = 10 | pages = 2506–2538 | date = October 2003 | pmid = 14667954 | doi = 10.1016/S0149-2918(03)80314-4 | citeseerx = 10.1.1.451.9407 }}</ref><ref>{{cite journal | vauthors = Bou Ghannam A, Pelak VS | title = Visual Snow: a Potential Cortical Hyperexcitability Syndrome | journal = Current Treatment Options in Neurology | volume = 19 | issue = 3 | article-number = 9 | date = March 2017 | pmid = 28349350 | doi = 10.1007/s11940-017-0448-3 | s2cid = 4829787 }}</ref> although a systematic review conducted in 2013 concluded that well-designed clinical trials have shown no benefit for lamotrigine in [[neuropathic pain]].<ref>{{cite journal | vauthors = Wiffen PJ, Derry S, Moore RA | title = Lamotrigine for chronic neuropathic pain and fibromyalgia in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 12 | article-number = CD006044 | date = December 2013 | pmid = 24297457 | pmc = 6485508 | doi = 10.1002/14651858.CD006044.pub4 }}</ref> Off-label psychiatric usage includes the treatment of treatment-resistant [[obsessive-compulsive disorder]],<ref name="pmid25969599">{{cite journal | vauthors = Hussain A, Dar MA, Wani RA, Shah MS, Jan MM, Malik YA, Chandel RK, Margoob MA | title = Role of lamotrigine augmentation in treatment-resistant obsessive compulsive disorder: a retrospective case review from South Asia | journal = Indian Journal of Psychological Medicine | volume = 37 | issue = 2 | pages = 154–158 | date = 2015 | pmid = 25969599 | pmc = 4418246 | doi = 10.4103/0253-7176.155613 | doi-access = free }}</ref> [[Depersonalization-derealization disorder|depersonalization derealization disorder]],<ref>{{Cite journal | vauthors = Medford N | title = Understanding and treating depersonalisation disorder | doi = 10.1192/apt.11.2.92 | journal = Advances in Psychiatric Treatment | volume = 11 | issue = 2 | pages = 92–100 | year = 2005 | doi-access = free }}</ref> [[hallucinogen persisting perception disorder]],<ref>{{cite journal | vauthors = Hermle L, Simon M, Ruchsow M, Geppert M | title = Hallucinogen-persisting perception disorder | journal = Therapeutic Advances in Psychopharmacology | volume = 2 | issue = 5 | pages = 199–205 | date = October 2012 | pmid = 23983976 | pmc = 3736944 | doi = 10.1177/2045125312451270 }}</ref> [[schizoaffective disorder]],<ref>{{cite journal | vauthors = Erfurth A, Walden J, Grunze H | title = Lamotrigine in the treatment of schizoaffective disorder | journal = Neuropsychobiology | volume = 38 | issue = 3 | pages = 204–205 | date = October 1998 | pmid = 9778612 | doi = 10.1159/000026540 | url = https://epub.ub.uni-muenchen.de/16560/1/10_1159_000026540.pdf | access-date = 9 September 2019 | url-status = live | s2cid = 46848204 | archive-url = https://web.archive.org/web/20210828140506/https://epub.ub.uni-muenchen.de/16560/1/10_1159_000026540.pdf | archive-date = 28 August 2021 }}</ref> and [[borderline personality disorder]].<ref>{{cite journal | vauthors = Lieb K, Völlm B, Rücker G, Timmer A, Stoffers JM | title = Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials | journal = The British Journal of Psychiatry | volume = 196 | issue = 1 | pages = 4–12 | date = January 2010 | pmid = 20044651 | doi = 10.1192/bjp.bp.108.062984 | doi-access = free }}</ref> It has not been shown to be useful in [[post-traumatic stress disorder]].<ref>{{cite journal | vauthors = Williams T, Phillips NJ, Stein DJ, Ipser JC | title = Pharmacotherapy for post traumatic stress disorder (PTSD) | journal = The Cochrane Database of Systematic Reviews | volume = 2022 | issue = 3 | article-number = CD002795 | date = March 2022 | pmid = 35234292 | pmc = 8889888 | doi = 10.1002/14651858.CD002795.pub3 }}</ref>

[[GlaxoSmithKline]] investigated lamotrigine for the treatment of [[ADHD]] with inconclusive results. No detrimental effects on [[cognition|cognitive function]] were observed; however, the only statistical improvement in core ADHD symptoms was an improvement on a [[Paced Auditory Serial Addition Test]] that measures auditory processing speed and calculation ability.<ref>{{cite web | work = Glaxo Smith Klein Clinical Study Register | id = Study No. LAM40120 | url = http://www.gsk-clinicalstudyregister.com/files2/1623.pdf | title = Lamotrigine (Lamictal) Treatment in adults with Attention Deficit Hyperactivity Disorder (ADHD), A pilot study | archive-url = https://web.archive.org/web/20171201131224/https://www.gsk-clinicalstudyregister.com/files2/1623.pdf | archive-date=1 December 2017 }}</ref> Another study reported that lamotrigine might be a safe and effective treatment option for adult ADHD [[Comorbidity|comorbid]] with bipolar and recurrent depression.<ref>{{cite journal | vauthors = Öncü B, Er O, Çolak B, Nutt DJ | title = Lamotrigine for attention deficit-hyperactivity disorder comorbid with mood disorders: a case series | journal = Journal of Psychopharmacology | volume = 28 | issue = 3 | pages = 282–283 | date = March 2014 | pmid = 23784736 | doi = 10.1177/0269881113493365 | s2cid = 8011752 }}</ref>

==Side effects==
Side effects such as rash, fever, and fatigue are very serious, as they may indicate incipient SJS, TEN, DRESS syndrome, or [[aseptic meningitis]].<ref name="drugs.com">{{Cite web | url=http://www.rxlist.com/lamictal-drug.htm | title=Lamictal (Lamotrigine): Uses, Dosage, Side Effects, Interactions, Warning | access-date=26 August 2016 | archive-date=27 August 2016 | archive-url=https://web.archive.org/web/20160827070255/http://www.rxlist.com/lamictal-drug.htm | url-status=live }}</ref>

Lamotrigine prescribing information has a [[black box warning]] about life-threatening skin reactions, including [[Stevens–Johnson syndrome]] (SJS), [[DRESS syndrome]], and [[toxic epidermal necrolysis]] (TEN).<ref name="Lamictal FDA label" /> The manufacturer states that nearly all cases appear in the first two to eight weeks of therapy.<ref name="Lamictal FDA label" /> Patients should seek medical attention for any unexpected skin rash, as its presence is an indication of a possible serious or even deadly side effect of the drug. Not all rashes that occur while taking lamotrigine progress to SJS or TEN. Between 5 and 10% of patients will develop a rash, but only one in a thousand patients will develop a serious rash. Rash and other skin reactions are more common in children, so this medication is often reserved for adults. For patients whose lamotrigine has been stopped after the development of a rash, rechallenge with lamotrigine is also a viable option. Usually, rechallenge is done by reinstating lamotrigine at a smaller dose (5mg/day). However, it does not apply to very serious cases.<ref>{{cite journal | vauthors = Serrani Azcurra DJ | title = Lamotrigine rechallenge after a skin rash. A combined study of open cases and a meta-analysis | journal = Revista de Psiquiatria y Salud Mental | volume = 6 | issue = 4 | pages = 144–149 | date = Jun 2012 | pmid = 23084805 | doi = 10.1016/j.rpsm.2012.04.002 | url = https://zenodo.org/record/895436 | access-date = 10 December 2019 | url-status = live | archive-url = https://web.archive.org/web/20210828140510/https://zenodo.org/record/895436/preview/article.pdf | archive-date = 28 August 2021 }}</ref> The incidence of these eruptions increases in patients who are currently on, or recently discontinued, a [[valproate]]-type anticonvulsant drug, as these medications interact in such a way that the clearance of both is decreased and the effective dose of lamotrigine is increased.<ref name="Lamictal FDA label" />

Lamotrigine has a 5-week graduated dosing schedule in order to prevent possible skin rashes.<ref>{{Cite web |title=Lamictal, Lamictal XR (lamotrigine) dosing, indications, interactions, adverse effects, and more |url=https://reference.medscape.com/drug/lamictal-lamotrigine-343012 |access-date=8 July 2025 |website=reference.medscape.com}}</ref><ref name = "Betchel_2025">{{cite book | vauthors = Betchel NT, Fariba KA, Saadabadi A | chapter = Lamotrigine |date=2025 |title = StatPearls | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK470442/ |access-date=8 July 2025 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29262021 }}</ref>

In 2018, the FDA required a new warning for the risk of [[hemophagocytic lymphohistiocytosis]]. This serious reaction can occur between days to weeks after starting the treatment.<ref>{{Cite web|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm605628.htm|title=Safety Alerts for Human Medical Products - Lamictal (lamotrigine): Drug Safety Communication - Serious Immune System Reaction|website=www.fda.gov|access-date=14 May 2018|archive-date=25 July 2018|archive-url=https://web.archive.org/web/20180725121507/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm605628.htm}}</ref>

Other side effects include [[Hair loss|alopecia]] (hair loss), loss of balance or coordination, [[diplopia|double vision]], [[strabismus|crossed eyes]], [[Miosis|pupil constriction]], [[blurred vision]], [[dizziness]] and [[Ataxia|lack of coordination]], [[Somnolence|drowsiness]], [[insomnia]], [[anxiety]], vivid dreams or [[nightmare]]s, [[dry mouth]], [[Mouth ulcer|mouth ulcers]], [[memory]] problems, [[Mood swing|mood changes]], [[Itch|itchiness]], [[Rhinorrhea|runny nose]], [[cough]], [[nausea]], [[indigestion]], [[abdominal pain]], [[weight loss]], missed or painful [[menstrual period]]s, and [[vaginitis]]. The side-effects profile varies for different patient populations.<ref name="drugs.com"/> Overall adverse effects in treatment are similar between men, women, geriatric, pediatric, and racial groups.<ref name="Lamictal FDA label" />

Lamotrigine has been associated with a decrease in white blood cell count ([[leukopenia]]).<ref name="pmid7888892">{{cite journal | vauthors = Nicholson RJ, Kelly KP, Grant IS | title = Leucopenia associated with lamotrigine | journal = BMJ | volume = 310 | issue = 6978 | page = 504 | date = February 1995 | pmid = 7888892 | pmc = 2548879 | doi = 10.1136/bmj.310.6978.504b }}</ref> Lamotrigine does not prolong [[QT interval|QT/QTc]] in TQT studies in healthy subjects.<ref>{{cite journal | vauthors = Dixon R, Job S, Oliver R, Tompson D, Wright JG, Maltby K, Lorch U, Taubel J | title = Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects | journal = British Journal of Clinical Pharmacology | volume = 66 | issue = 3 | pages = 396–404 | date = September 2008 | pmid = 18662287 | pmc = 2526242 | doi = 10.1111/j.1365-2125.2008.03250.x | url = http://www.richmondpharmacology.com/downloads/Publications/Lamotrigine%20does%20not%20prolong%20QTc%20in%20a%20thorough%20QTQTc%20study%20in%20healthy%20subjects.pdf | archive-url = https://web.archive.org/web/20170809114208/http://www.richmondpharmacology.com/downloads/Publications/Lamotrigine%20does%20not%20prolong%20QTc%20in%20a%20thorough%20QTQTc%20study%20in%20healthy%20subjects.pdf | archive-date = 9 August 2017 }}</ref>

In people taking antipsychotics, cases of lamotrigine-precipitated [[neuroleptic malignant syndrome]] have been reported.<ref>{{cite journal | vauthors = Motomura E, Tanii H, Usami A, Ohoyama K, Nakagawa M, Okada M | title = Lamotrigine-induced neuroleptic malignant syndrome under risperidone treatment: a case report | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 24 | issue = 2 | pages = E38–E39 | date = March 2012 | pmid = 22772697 | doi = 10.1176/appi.neuropsych.11040093 }}</ref><ref>{{cite journal | vauthors = Ishioka M, Yasui-Furukori N, Hashimoto K, Sugawara N | title = Neuroleptic malignant syndrome induced by lamotrigine | journal = Clinical Neuropharmacology | volume = 36 | issue = 4 | pages = 131–132 | date = July–August 2013 | pmid = 23783003 | doi = 10.1097/WNF.0b013e318294799a | s2cid = 19508393 }}</ref>

===Women===
Women are more likely than men to have side effects.<ref name="Lamictal FDA label" />

Some evidence shows interactions between lamotrigine and female hormones, which can be of particular concern for women on estrogen-containing [[hormonal contraceptives]]. [[Ethinylestradiol]], an ingredient of such contraceptives, has been shown to decrease serum levels of lamotrigine.<ref name="reimers">{{cite journal | vauthors = Reimers A, Helde G, Brodtkorb E | title = Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations | journal = Epilepsia | volume = 46 | issue = 9 | pages = 1414–1417 | date = September 2005 | pmid = 16146436 | doi = 10.1111/j.1528-1167.2005.10105.x | s2cid = 7408965 | doi-access = free }}</ref> Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Likewise, women may experience an increase in lamotrigine side effects upon discontinuation of birth control pills. This may include the "pill-free" week where lamotrigine serum levels have been shown to increase twofold.<ref name="Lamictal FDA label" />

Many studies have found no association between lamotrigine exposure ''in utero'' and birth defects, while those that have found an association have found only slight associations with minor malformations such as [[cleft palates]].<ref name="TGA">{{cite web|title=Product Information Lamotrigine Sandoz 25mg, 50mg, 100mg, 200mg, Dispersible/Chewable Tablets|website=TGA eBusiness Services|publisher=Sandoz Pty Ltd|date=10 January 2017|access-date=23 August 2017|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2015-PI-02602-1|archive-date=23 August 2017|archive-url=https://web.archive.org/web/20170823204339/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2015-PI-02602-1|url-status=live}}</ref> Review studies have found that overall rates of congenital malformations in infants exposed to lamotrigine ''in utero'' are relatively low (1–4%), which is similar to the rate of malformations in the general population.<ref>{{cite journal | vauthors = Berwaerts K, Sienaert P, De Fruyt J | title = [Teratogenic effects of lamotrigine in women with bipolar disorder] | language = nl | journal = Tijdschrift voor Psychiatrie | volume = 51 | issue = 10 | pages = 741–750 | year = 2009 | pmid = 19821242 }}</ref><ref>{{cite journal | vauthors = Prabhu LV, Nasar MA, Rai R, Madhyastha S, Singh G | title = Lamotrigine in pregnancy: safety profile and the risk of malformations | journal = Singapore Medical Journal | volume = 48 | issue = 10 | pages = 880–883 | date = October 2007 | pmid = 17909669 }}</ref> It is known that lamotrigine is a weak inhibitor of human [[dihydrofolate reductase]] (DHFR) and other, more powerful, human DHFR inhibitors such as [[methotrexate]] are known to be [[teratogenic]].<ref name="TGA"/>

Lamotrigine is expressed in [[breast milk]]; the manufacturer recommends carefully weighing the benefits and risks of taking lamotrigine while [[breastfeeding]].<ref>{{Cite web |date=February 2023 |title=Prescribing information, Lamictal |url=https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Lamictal/pdf/LAMICTAL-PI-MG.PDF |access-date=25 April 2023 |publisher=GSK |language=en |archive-date=23 March 2023 |archive-url=https://web.archive.org/web/20230323052319/https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Lamictal/pdf/LAMICTAL-PI-MG.PDF |url-status=live }}</ref> However, some studies suggest that lamotrigine is safe to use while breastfeeding.<ref>{{cite journal | vauthors = Dalili H, Nayeri F, Shariat M, Asgarzadeh L | title = Lamotrigine effects on breastfed infants | journal = Acta Medica Iranica | volume = 53 | issue = 7 | pages = 393–394 | date = July 2015 | pmid = 26520624 }}</ref>  A frequently updated review of scientific literature rates lamotrigine as L3: moderately safe.<ref>{{cite book |title=Medications and Mothers' Milk | vauthors = Hale TW |year=2008 |publisher=Hale Publishing|isbn=978-0-9815257-2-3 |page=532 |edition=13th}}</ref>

===Other types of effects===
Lamotrigine binds to [[melanin]]-containing tissues such as the iris of the eye or melanin-rich skin. The long-term consequences of this are unknown.<ref>{{cite web|url=https://www.rxlist.com/lamictal-drug.htm#warnings|title=Lamictal, Warnings & Precautions |publisher=RxList Inc.|access-date=2 November 2020|archive-date=29 June 2021|archive-url=https://web.archive.org/web/20210629110648/https://www.rxlist.com/lamictal-drug.htm#warnings|url-status=live}}</ref>

Lamotrigine is known to affect sleep. Studies with small numbers of patients (10–15) reported that lamotrigine increases the duration of [[Rapid eye movement sleep|REM sleep]], decreases the number of phase shifts, and decreases the duration of [[slow-wave sleep]],<ref>{{cite journal | vauthors = Foldvary N, Perry M, Lee J, Dinner D, Morris HH | title = The effects of lamotrigine on sleep in patients with epilepsy | journal = Epilepsia | volume = 42 | issue = 12 | pages = 1569–1573 | date = December 2001 | pmid = 11879368 | doi = 10.1046/j.1528-1157.2001.46100.x | s2cid = 12218913 | doi-access = free }}</ref> and that there was no effect on [[Vigilance (psychology)|vigilance]],<ref>{{cite journal | vauthors = Bonanni E, Galli R, Gori S, Pasquali L, Maestri M, Iudice A, Murri L | title = Neurophysiological evaluation of vigilance in epileptic patients on monotherapy with lamotrigine | journal = Clinical Neurophysiology | volume = 112 | issue = 6 | pages = 1018–1022 | date = June 2001 | pmid = 11377260 | doi = 10.1016/S1388-2457(01)00537-5 | s2cid = 6983433 | hdl = 11568/186375 }}</ref> daytime somnolence and cognitive function.<ref>{{cite journal | vauthors = Placidi F, Marciani MG, Diomedi M, Scalise A, Pauri F, Giacomini P, Gigli GL | title = Effects of lamotrigine on nocturnal sleep, daytime somnolence and cognitive functions in focal epilepsy | journal = Acta Neurologica Scandinavica | volume = 102 | issue = 2 | pages = 81–86 | date = August 2000 | pmid = 10949523 | doi = 10.1034/j.1600-0404.2000.102002081.x | s2cid = 24323287 }}</ref> However, a retrospective study of 109 patients' medical records found that 6.7% of patients experienced an "alerting effect" resulting in intolerable [[insomnia]], for which the treatment had to be discontinued.<ref>{{cite journal | vauthors = Sadler M | title = Lamotrigine associated with insomnia | journal = Epilepsia | volume = 40 | issue = 3 | pages = 322–325 | date = March 1999 | pmid = 10080513 | doi = 10.1111/j.1528-1157.1999.tb00712.x | s2cid = 43902298 | doi-access = free }}</ref>

Lamotrigine can induce a type of seizure known as a [[myoclonic jerk]], which tends to happen soon after the use of the medication.<ref>{{cite web | title = Review: could Lamictal cause Myoclonic jerks? | url = http://www.ehealthme.com/ds/lamictal/myoclonic+jerks | work = eHealthMe | date = 2016 | archive-url = https://web.archive.org/web/20160129020525/http://www.ehealthme.com/ds/lamictal/myoclonic+jerks | archive-date=29 January 2016 }}</ref> When used in the treatment of myoclonic epilepsies such as [[juvenile myoclonic epilepsy]], lower doses (and lower plasma levels) are usually needed, as even moderate doses of this drug can induce seizures, including tonic-clonic seizures, which can develop into [[status epilepticus]], which is a medical emergency. It can also cause myoclonic status epilepticus.<ref name="Lamictal FDA label" />

In overdose, lamotrigine can cause uncontrolled seizures in most people. Reported results in overdoses involving up to 15&nbsp;g include increased seizures, coma, and death.<ref name="Lamictal FDA label" />

==Pharmacology==
===Mechanism of action===
Lamotrigine is a member of the [[sodium channel blocking]] class of antiepileptic drugs.<ref>{{cite book | vauthors = Rogawski M | veditors=Levy RH, Mattson RH, Meldrum BS, Perucca E |title=Antiepileptic Drugs, Fifth Edition|publisher=Lippincott Williams & Wilkins |year=2002 |pages=3–22 |chapter=Chapter 1: Principles of antiepileptic drug action |isbn= 978-0-7817-2321-3}}</ref> This may suppress the release of [[glutamate]] and [[aspartate]], two dominant excitatory neurotransmitters in the central nervous system.<ref name="Lamictal FDA label" /> It is generally accepted to be a member of the sodium channel blocking class of [[antiepileptic drugs]],<ref>{{cite journal | vauthors = Rogawski MA, Löscher W | title = The neurobiology of antiepileptic drugs | journal = Nature Reviews. Neuroscience | volume = 5 | issue = 7 | pages = 553–564 | date = July 2004 | pmid = 15208697 | doi = 10.1038/nrn1430 | url = https://zenodo.org/record/1233562 | access-date = 31 August 2020 | url-status = live | s2cid = 2201038 | archive-url = https://web.archive.org/web/20201216114030/https://zenodo.org/record/1233562 | archive-date = 16 December 2020 }}</ref> but it could have additional actions, since it has a broader spectrum of action than other sodium channel antiepileptic drugs such as [[phenytoin]] and is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel-blocking antiepileptic drugs are not, possibly on account of its [[sigma receptor]] activity. In addition, lamotrigine shares few side effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties.<ref name= pmid7687190>{{cite journal | vauthors = Lees G, Leach MJ | title = Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neurological cultures from rat cortex | journal = Brain Research | volume = 612 | issue = 1–2 | pages = 190–199 | date = May 1993 | pmid = 7687190 | doi = 10.1016/0006-8993(93)91660-K | s2cid = 20535234 }}</ref>

It is a [[triazine]] derivate that inhibits [[voltage-gated ion channel|voltage-sensitive]] [[sodium channels]], leading to [[Membrane stabilizing effect|stabilization of neuronal membranes]]. It also blocks L-, N-, and P-type [[calcium channel]]s and weakly inhibits the serotonin [[5-HT3 receptor|5-HT<sub>3</sub> receptor]].<ref>{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s14s18s19s20lbl.pdf|title=Prescribing Information for LAMICTAL (lamotrigine)|website=FDA|access-date=12 January 2020|archive-date=12 January 2020|archive-url=https://web.archive.org/web/20200112201226/https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020241s10s21s25s26s27,020764s3s14s18s19s20lbl.pdf|url-status=live}}</ref> These actions are thought to inhibit release of [[glutamate]] at cortical projections in the [[ventral striatum]] [[limbic system|limbic areas]],<ref>{{cite journal | vauthors = Thomas SP, Nandhra HS, Jayaraman A | title = Systematic review of lamotrigine augmentation of treatment resistant unipolar depression (TRD) | journal = Journal of Mental Health | volume = 19 | issue = 2 | pages = 168–175 | date = April 2010 | pmid = 20433324 | doi = 10.3109/09638230903469269 | s2cid = 39871557 }}</ref> and its [[neuroprotection|neuroprotective]] and antiglutamatergic effects have been pointed out as promising contributors to its mood stabilizing activity.<ref>{{cite journal | vauthors = Ketter TA, Manji HK, Post RM | title = Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders | journal = Journal of Clinical Psychopharmacology | volume = 23 | issue = 5 | pages = 484–495 | date = October 2003 | pmid = 14520126 | doi = 10.1097/01.jcp.0000088915.02635.e8 | s2cid = 35902870 }}</ref> Observations that lamotrigine reduced [[GABAA receptor|GABA<sub>A</sub> receptor]]-mediated neurotransmission in rat amygdala suggest that a [[GABA|GABAergic]] mechanism may also be involved.<ref>{{cite journal | vauthors = Braga MF, Aroniadou-Anderjaska V, Post RM, Li H | title = Lamotrigine reduces spontaneous and evoked GABAA receptor-mediated synaptic transmission in the basolateral amygdala: implications for its effects in seizure and affective disorders | journal = Neuropharmacology | volume = 42 | issue = 4 | pages = 522–529 | date = March 2002 | pmid = 11955522 | doi = 10.1016/s0028-3908(01)00198-8 | s2cid = 26174058 }}</ref> It appears that lamotrigine does not increase GABA blood levels in humans.<ref>{{cite journal | vauthors = Shiah IS, Yatham LN, Gau YC, Baker GB | title = Effect of lamotrigine on plasma GABA levels in healthy humans | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 27 | issue = 3 | pages = 419–423 | date = May 2003 | pmid = 12691776 | doi = 10.1016/S0278-5846(03)00028-9 | s2cid = 19209195 }}</ref>

Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors that anticonvulsants affect ([[adrenergic]], [[dopamine]] [[Dopamine receptor D1|D<sub>1</sub>]] and [[Dopamine receptor D2|D<sub>2</sub>]], [[muscarinic]], [[GABA]], [[histaminergic]] [[Histamine H1 receptor|H<sub>1</sub>]], [[serotonin]] [[5-HT2|5-HT<sub>2</sub>]], and [[N-methyl-D-aspartate]]). Inhibitory effects on [[5-HT]], [[norepinephrine]], and dopamine transporters are weak. According to the article, the IC<sub>50</sub> values are 240μM (5-HT, human platelets), 474 μM (5-HT, rat brain synaptosomes), 239 μM (norepinephrine) and 322 μM (dopamine).<ref>{{cite journal | vauthors = Southam E, Kirkby D, Higgins GA, Hagan RM | title = Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats | journal = European Journal of Pharmacology | volume = 358 | issue = 1 | pages = 19–24 | date = September 1998 | pmid = 9809864 | doi = 10.1016/s0014-2999(98)00580-9 }}</ref> Lamotrigine blocks NMDA receptor-initiated [[arachidonic acid]] signalling in rat brain.<ref>{{cite journal | title=Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: Implications for its efficacy in bipolar disorder | date=28 June 2011 | doi=10.1017/S1461145711001003 | pmc=3204186 | journal=The International Journal of Neuropsychopharmacology | volume=15 | issue=7 | pages=931–943 | pmid=21733229 | vauthors = Ramadan E, Basselin M, Rao JS, Chang L, Chen M, Ma K, Rapoport SI }}</ref> Lamotrigine is a weak inhibitor of [[dihydrofolate reductase]],<ref name="Lamictal FDA label">{{cite web | title=Lamictal- lamotrigine tablet Lamictal- lamotrigine tablet, for suspension Lamictal ODT- lamotrigine tablet, orally disintegrating Lamictal- lamotrigine kit | website=DailyMed | date=13 April 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7e3572d-56fe-4727-2bb4-013ccca22678 | access-date=27 August 2022 | archive-date=27 August 2022 | archive-url=https://web.archive.org/web/20220827011235/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7e3572d-56fe-4727-2bb4-013ccca22678 | url-status=live }}</ref> but whether this effect is sufficient to contribute to a mechanism of action or increases risk to the fetus during pregnancy is not known. Early studies of lamotrigine's mechanism of action examined its effects on the release of endogenous amino acids from rat cerebral cortex slices ''in vitro''. As is the case for antiepileptic drugs that act on voltage-dependent sodium channels, lamotrigine thereby inhibits the release of [[glutamate]] and [[aspartate]], which is evoked by the sodium-channel activator [[veratrine]] and was less effective in the inhibition of [[acetylcholine]] or [[GABA]] release. At high concentrations, it did not affect spontaneous or [[potassium]]-evoked amino acid release.<ref name="Lamictal FDA label" />

These studies suggested that lamotrigine acts presynaptically on voltage-gated sodium channels to decrease glutamate release. Several electrophysiological studies have investigated the effects of lamotrigine on voltage-gated sodium channels. For example, lamotrigine blocked sustained repetitive firing in cultured mouse spinal cord neurons in a concentration-dependent manner, at concentrations that are therapeutically relevant in the treatment of human seizures. In cultured hippocampal neurons, lamotrigine reduced sodium currents in a voltage-dependent manner, and at depolarised potentials showed a small frequency-dependent inhibition. These and a variety of other results indicate that the antiepileptic effect of lamotrigine, like those of phenytoin and [[carbamazepine]], is at least in part due to use- and voltage-dependent modulation of fast voltage-dependent sodium currents. However, lamotrigine has a broader clinical spectrum of activity than phenytoin and carbamazepine and is recognized to be protective against generalized [[absence epilepsy]] and other generalized epilepsy syndromes, including primary generalized tonic-clonic seizures, juvenile myoclonic epilepsy, and Lennox-Gastaut syndrome.

The basis for this broader spectrum of activity of lamotrigine is unknown but could relate to actions of the drug on [[Voltage-dependent calcium channel|voltage-gated calcium channels]]. Lamotrigine blocks T-type [[calcium channels]] weakly, if at all. However, it does inhibit native and recombinant high voltage-gated calcium channels (N- and P/Q/R-types) at therapeutic concentrations. Whether this activity on calcium channels accounts for lamotrigine's broader clinical spectrum of activity in comparison with phenytoin and carbamazepine remains to be determined.

===Pharmacokinetics===
The [[pharmacokinetics]] of lamotrigine follow [[first-order kinetics]], with a [[half-life]] of 29 hours and volume of distribution of 1.36{{nbsp}}L/kg.<ref>{{cite journal | vauthors = Ramsay RE, Pellock JM, Garnett WR, Sanchez RM, Valakas AM, Wargin WA, Lai AA, Hubbell J, Chern WH, Allsup T | title = Pharmacokinetics and safety of lamotrigine (Lamictal) in patients with epilepsy | journal = Epilepsy Research | volume = 10 | issue = 2–3 | pages = 191–200 | year = 1991 | pmid = 1817959 | doi = 10.1016/0920-1211(91)90012-5 | s2cid = 34525226 }}</ref> Lamotrigine is rapidly and completely absorbed after oral administration. Its absolute [[bioavailability]] is 98% and its plasma [[Cmax (pharmacology)|C<sub>max</sub>]] occurs from 1.4 to 4.8 hours. Available data indicate that its bioavailability is not affected by food. Estimate of the mean apparent volume of distribution of lamotrigine following oral administration ranges from 0.9 to 1.3{{nbsp}}L/kg. This is independent of dose and is similar to following single and multiple doses in both patients with epilepsy and in healthy volunteers.<ref>{{cite journal | vauthors = Cohen AF, Land GS, Breimer DD, Yuen WC, Winton C, Peck AW | title = Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans | journal = Clinical Pharmacology and Therapeutics | volume = 42 | issue = 5 | pages = 535–541 | date = November 1987 | pmid = 3677542 | doi = 10.1038/clpt.1987.193 | s2cid = 19710948 }}</ref>

Lamotrigine is inactivated by [[glucuronidation]] in the [[liver]].<ref>{{cite journal | vauthors = Werz MA | title = Pharmacotherapeutics of epilepsy: use of lamotrigine and expectations for lamotrigine extended-release | journal = Therapeutics and Clinical Risk Management | volume = 4 | issue = 5 | pages = 1035–1046 | date = October 2008 | pmid = 19209284 | pmc = 2621406 | doi = 10.2147/TCRM.S3343 | doi-access = free }}</ref> Lamotrigine is metabolized predominantly by [[glucuronic acid]] [[conjugation (biochemistry)|conjugation]]. Its major metabolite is an inactive 2-n-glucuronide conjugate.<ref>{{cite journal | vauthors = Goa KL, Ross SR, Chrisp P | title = Lamotrigine. A review of its pharmacological properties and clinical efficacy in epilepsy | journal = Drugs | volume = 46 | issue = 1 | pages = 152–176 | date = July 1993 | pmid = 7691504 | doi = 10.2165/00003495-199346010-00009 }}</ref>

Lamotrigine has fewer drug interactions than many [[anticonvulsant]] drugs, although pharmacokinetic interactions with [[carbamazepine]], [[phenytoin]] and other hepatic enzyme-inducing medications may shorten [[half-life]].<ref>{{cite journal | vauthors = Anderson GD | title = A mechanistic approach to antiepileptic drug interactions | journal = The Annals of Pharmacotherapy | volume = 32 | issue = 5 | pages = 554–563 | date = May 1998 | pmid = 9606477 | doi = 10.1345/aph.17332 | s2cid = 43441971 }}</ref> Dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance.<ref name="Lamictal FDA label" />

The capacity of available tests to detect potentially adverse consequences of [[melanin]] binding is unknown. Clinical trials excluded subtle effects and optimal duration of treatment.  There are no specific recommendations for periodic ophthalmological monitoring. Lamotrigine binds to the eye and melanin-containing tissues which can accumulate over time and may cause toxicity. Prescribers should be aware of the possibility of long-term ophthalmologic effects and base treatment on clinical response.  Patient compliance should be periodically reassessed with lab and medical testing of liver and kidney function to monitor progress or side effects.<ref name="Lamictal FDA label" />

==Chemistry==
The first synthesis of lamotrigine was disclosed in a patent file by the [[Wellcome Trust|Wellcome Foundation]] in 1980.<ref name=CA1112643>{{cite patent |country=CA |number=1112643 |status=patent |pubdate=1981-11-17 |fdate=1980-05-30 |pridate=1981-03-16 |inventor=Baxter MG, Sawyer DA, Miller AA, Elphick AR |title=3,5-diamino-6-phenyl-1,2,4-triazines |assign1=Wellcome Foundation Ltd }}</ref><ref>{{cite journal |doi=10.1021/acs.oprd.7b00262 |title=An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine |year=2017 | vauthors = Leitch DC, John MP, Slavin PA, Searle AD |journal=Organic Process Research & Development |volume=21 |issue=11 |pages=1815–1821 }}</ref>
2,3-Dichlorobenzoyl chloride is treated with [[cuprous cyanide]] to form an [[acyl cyanide]]. This is then reacted with the [[nitrate]] salt of [[aminoguanidine]] to give an intermediate which is cyclised to the diamino [[triazine]] of the drug product.<ref>{{cite journal | vauthors = Kitson PJ, Marie G, Francoia JP, Zalesskiy SS, Sigerson RC, Mathieson JS, Cronin L | title = Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals | journal = Science | volume = 359 | issue = 6373 | pages = 314–319 | date = January 2018 | pmid = 29348235 | doi = 10.1126/science.aao3466 | url = http://eprints.gla.ac.uk/156447/1/156447.pdf | access-date = 21 April 2023 | url-status = live | s2cid = 206663094 | bibcode = 2018Sci...359..314K | archive-url = https://web.archive.org/web/20230421120743/http://eprints.gla.ac.uk/156447/1/156447.pdf | archive-date = 21 April 2023 }}</ref>
:[[File:Lamotrigine synthesis CA1112643.svg|class=skin-invert-image|600px]]

==History==
* 1980 — initial patent filings are made by the Wellcome Foundation.<ref name=CA1112643/> 
* 1990 — lamotrigine is approved for use in Ireland to treat epilepsy.<ref name="pmid 18001843">{{cite journal | vauthors = Weisler RH, Calabrese JR, Bowden CL, Ascher JA, DeVeaugh-Geiss J, Evoniuk G | title = Discovery and development of lamotrigine for bipolar disorder: a story of serendipity, clinical observations, risk-taking, and persistence | journal = Journal of Affective Disorders | volume = 108 | issue = 1–2 | pages = 1–9 | date = May 2008 | pmid = 18001843 | doi = 10.1016/j.jad.2007.09.012 }}</ref>
* 1991 — lamotrigine is used in the United Kingdom as an anticonvulsant medication<ref>{{cite book | vauthors = Engel J  |title=Seizures and Epilepsy |date=2013 |publisher=OUP USA |isbn=978-0-19-532854-7 |page=567 |url=https://books.google.com/books?id=5PgjmjugIX8C&pg=PA567 |access-date=31 August 2020 |archive-date=2 August 2021 |archive-url=https://web.archive.org/web/20210802113953/https://books.google.com/books?id=5PgjmjugIX8C&pg=PA567 |url-status=live }}</ref>
* December 1994 — lamotrigine was approved for use in the United States for the treatment of [[partial seizures]].<ref name="anonymous">{{cite web|url=https://www.fda.gov/cder/rdmt/ESCY03AP.HTM|title=EFFICACY SUPPLEMENTS APPROVED IN CALENDAR YEAR 2003|date=19 March 2004|publisher=FDA/Center for Drug Evaluation and Research|access-date=9 April 2008|archive-date=21 February 2008|archive-url=https://web.archive.org/web/20080221185906/http://www.fda.gov/cder/rdmt/ESCY03AP.HTM}}</ref>
* August 1998 — for use as adjunctive treatment of [[Lennox-Gastaut syndrome]] in pediatric and adult patients, new dosage form: chewable dispersible tablets.{{citation needed|date=August 2022}}
* December 1998 — for use as monotherapy for the treatment of partial seizures in adult patients when converting from a single enzyme-inducing anticonvulsant drug.{{citation needed|date=August 2022}}
* January 2003 — for use as adjunctive therapy for partial seizures in pediatric patients as young as two years of age.
* June 2003 — approved for maintenance treatment of [[bipolar II disorder]]; the first such medication since [[lithium pharmacology|lithium]].{{citation needed|date=August 2022}}
* January 2004 — for use as monotherapy for the treatment of partial seizures in adult patients when converting from the anti-epileptic drug [[valproate]] (including [[valproic acid]]){{citation needed|date=August 2022}}

==Society and culture==

===Brand names===
Lamotrigine is sold under the original brand name Lamictal<ref name="Lamictal FDA label" /> and it is available in generic form under many brand names worldwide.<ref name=brands>{{cite web|title=Lamotrigine|url=https://www.drugs.com/international/lamotrigine.html|website=Drugs.com|access-date=9 December 2017|archive-date=10 December 2017|archive-url=https://web.archive.org/web/20171210072144/https://www.drugs.com/international/lamotrigine.html|url-status=live}}</ref><ref>{{cite web|url=http://www.dh.gov.uk/en/Healthcare/Medicinespharmacyandindustry/Prescriptions/DH_4104966|archive-url=http://webarchive.nationalarchives.gov.uk/20120524031414/http://www.dh.gov.uk/en/Healthcare/Medicinespharmacyandindustry/Prescriptions/DH_4104966|archive-date= 24 May 2012|title=Treatment for epilepsy: generic lamotrigine|author=<!-- Not stated --> |date=2 March 2005|publisher=Department of Health (UK)|access-date=9 April 2008}}</ref>

Lamotrigine is also available in 5-week starter "convenience packs" to help patients with the graduated dosing schedule.<ref name = "Betchel_2025" />

== Regulatory advisory in 2021 ==
In March 2021, the United States Food and Drug Administration (FDA) issued a warning regarding the potential for [[Arrhythmia|cardiac arrhythmias]] in people with pre-existing structural or conduction heart defects.<ref name="GlaxoSmithKline_2021">{{Cite web |title=Lamictal Prescribing Information |url=https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Lamictal/pdf/LAMICTAL-PI-MG.PDF |access-date=25 October 2022 |publisher=GlaxoSmithKline |publication-date=2021 |archive-date=26 October 2022 |archive-url=https://web.archive.org/web/20221026033218/https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Lamictal/pdf/LAMICTAL-PI-MG.PDF |url-status=live }}</ref><ref name="FDA Drug Safety Podcast_2022">{{Cite news |date=20 January 2022 |title=Studies show increased risk of heart rhythm problems with seizure and mental health medicine lamotrigine (Lamictal) in patients with heart disease |work=FDA Drug Safety Podcast |url=https://www.fda.gov/drugs/fda-drug-safety-podcasts/studies-show-increased-risk-heart-rhythm-problems-seizure-and-mental-health-medicine-lamotrigine |access-date=25 October 2022 |archive-date=26 October 2022 |archive-url=https://web.archive.org/web/20221026033216/https://www.fda.gov/drugs/fda-drug-safety-podcasts/studies-show-increased-risk-heart-rhythm-problems-seizure-and-mental-health-medicine-lamotrigine }}</ref> The warning provoked consternation and controversy within the professional community.<ref>{{cite journal | vauthors = Auerbach DS, Muniz CF | title = Cardiac Safety of Lamotrigine: Still Awaiting a Verdict | journal = Neurology | volume = 98 | issue = 17 | pages = 697–698 | date = April 2022 | pmid = 35260441 | doi = 10.1212/WNL.0000000000200189 | s2cid = 247316861 }}</ref> An ''[[in vitro]]'' study conducted in 2011 predicted Class IB antiarrhythmic activity at therapeutic concentrations of lamotrigine, due to its sodium channel-blocking activity.<ref>{{cite journal | vauthors = Harmer AR, Valentin JP, Pollard CE | title = On the relationship between block of the cardiac Na⁺ channel and drug-induced prolongation of the QRS complex | journal = British Journal of Pharmacology | volume = 164 | issue = 2 | pages = 260–273 | date = September 2011 | pmid = 21480866 | pmc = 3174407 | doi = 10.1111/j.1476-5381.2011.01415.x }}</ref> Thus, lamotrigine use in at-risk populations could prolong the QRS interval on the electrocardiogram, and increase the risk of arrhythmias and sudden death. No references to human studies or postmarket data in at-risk populations (i.e., people with structural heart disease) were cited to support the warning. A study in dogs is mentioned in the prescribing information brochure by the manufacturer.<ref name="GlaxoSmithKline_2021" /> A rapid systematic review concluded that "there is insufficient evidence to support or refute that lamotrigine is associated with sudden death or electrocardiogram changes..."<ref>{{cite journal | vauthors = Bunschoten JW, Husein N, Devinsky O, French JA, Sander JW, Thijs RD, Keezer MR | title = Sudden Death and Cardiac Arrythmia With Lamotrigine: A Rapid Systematic Review | journal = Neurology | volume = 98 | issue = 17 | pages = e1748–e1760 | date = April 2022 | pmid = 35260442 | doi = 10.1212/WNL.0000000000200164 | s2cid = 247317933 }}</ref> The FDA has recommended that further studies are conducted with lamotrigine and other sodium-channel blocking antiseizure medications.<ref name="FDA Drug Safety Podcast_2022" />{{Clear}}

In March 2023, an [[FDA Adverse Event Reporting System]] analysis demonstrated signals of [[cardiac arrest]], but not of [[tachyarrhythmia]] or [[bradyarrhythmia]] nor their clinical manifestation as fainting in lamotrigine. The study stratified the epileptic and psychiatric indications, explaining that the nature of the signal for cardiac arrest seems to be confounded by the psychiatric indication, which included 2.5 times more concomitant medications with cardiac adverse events, such as QT-prolonging drugs. Additionally, a 1.5-fold greater reports on [[Drug overdose|overdose]] and [[Suicide attempt|suicide attempts]] was recorded in the psychiatric reports. Although lamotrigine blocks the cardiac sodium channels at therapeutically relevant concentrations, owing to its short-fast kinetics at the channel level, this blockage did not translate into a disproportional signal in this study.<ref>{{cite journal | vauthors = Aboukaoud M, Wilf-Yarkoni A, Maor E | title = Investigation of cardiac arrhythmia events in patients treated with lamotrigine: FDA adverse event reporting system analysis | journal = Epilepsia | volume = 64 | issue = 9 | pages = 2322–2329 | date = September 2023 | pmid = 37350356 | doi = 10.1111/epi.17696 | s2cid = 259231884 | doi-access = free }}</ref>

== Research ==
Though lamotrigine has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Adverse effects were rarely severe enough for the medication to be discontinued in this age group, however, its effectiveness in reducing seizures was inconclusive.<ref>{{Cite report | vauthors = Treadwell JR, Wu M, Tsou AY | title = Management of Infantile Epilepsies [Internet]. | location = Rockville (MD) | publisher = Agency for Healthcare Research and Quality (US) | date = October 2022 | id = Report No.: 22(23)-EHC004 2021-SR-01 |url=https://effectivehealthcare.ahrq.gov/products/management-infantile-epilepsy/research |access-date=12 July 2023 |doi=10.23970/ahrqepccer252 |pmid=36383706 |s2cid=254357105 | url-access = subscription }}</ref>

== References ==
{{Reflist}}

{{Anticonvulsants}}
{{Mood stabilizers|z=s}}
{{Neuropathic pain and fibromyalgia pharmacotherapies}}
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