Lamotrigine is considered a first-line drug for primary generalizedtonic-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 asabsence seizure,myoclonic seizure, andatonic seizures.[17][18] 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.[19] 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.[19] Evidence supporting the use of lamotrigine as an add-on therapy fordrug-resistant focal epilepsy found that it is likely effective for reducing seizure frequency and is generally well tolerated.[20] Lamotrigine has some side effects including a risk of dizziness, nausea, ataxia, or visual disturbances such asdiplopia.[20] The long-term effects of lamotrigine have not been investigated.[20]
Lamotrigine is one of a small number of FDA-approved therapies for the form ofepilepsy known asLennox–Gastaut syndrome.[21] It reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks.[22] Combination withvalproate is common, but this increases the risk ofStevens–Johnson syndrome, and necessitates reduced dosing due to the interaction of these drugs.[23]
Lamotrigine is approved in the US for maintenance treatment ofbipolar I disorder andbipolar II disorder.[24] While the anticonvulsantscarbamazepine andvalproate are predominantlyantimanics, 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.[25] Lamotrigine has been shown to be as effective aslithium, the standard treatment for bipolar disorder.[26]
Lamotrigine has not demonstrated clear efficacy in treating acute mood episodes, either mania or depression. It has not demonstrated effectiveness in treating acute mania,[27] and there is controversy regarding the drug's effectiveness in treating acute bipolar depression.[28] 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 reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines, and it concludes that lamotrigine has "very limited, if any, efficacy in the treatment of acute bipolar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".[25] A 2008 paper by Calabrese et al. examined much of the same data, and found that in fiveplacebo-controlled studies, lamotrigine did not significantly differ from placebo in the treatment of bipolar depression.[29] 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 anumber needed to treat (NNT) of 11, or 7 in severe depression.[30]
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.[31]
Lamotrigine, as a monotherapy, is not substantially effective againstschizophrenia. However, various publications[32][33] and textbooks[34][35] have expressed that lamotrigine could be added toclozapine 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 withantipsychotics other thanclozapine, such asolanzapine,risperidone,haloperidol, andzuclopenthixol.[36]
GlaxoSmithKline investigated lamotrigine for the treatment ofADHD with inconclusive results. No detrimental effects oncognitive function were observed; however, the only statistical improvement in core ADHD symptoms was an improvement on aPaced Auditory Serial Addition Test that measures auditory processing speed and calculation ability.[48] Another study reported that lamotrigine might be a safe and effective treatment option for adult ADHDcomorbid with bipolar and recurrent depression.[49]
Side effects such as rash, fever, and fatigue are very serious, as they may indicate incipient SJS, TEN, DRESS syndrome, oraseptic meningitis.[50]
Lamotrigine prescribing information has ablack box warning about life-threatening skin reactions, includingStevens–Johnson syndrome (SJS),DRESS syndrome, andtoxic epidermal necrolysis (TEN).[4] The manufacturer states that nearly all cases appear in the first two to eight weeks of therapy.[4] 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.[51] The incidence of these eruptions increases in patients who are currently on, or recently discontinued, avalproate-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.[4]
Lamotrigine has a 5-week graduated dosing schedule in order to prevent possible skin rashes.[52][53]
In 2018, the FDA required a new warning for the risk ofhemophagocytic lymphohistiocytosis. This serious reaction can occur between days to weeks after starting the treatment.[54]
Lamotrigine has been associated with a decrease in white blood cell count (leukopenia).[55] Lamotrigine does not prolongQT/QTc in TQT studies in healthy subjects.[56]
Women are more likely than men to have side effects.[4]
Some evidence shows interactions between lamotrigine and female hormones, which can be of particular concern for women on estrogen-containinghormonal contraceptives.Ethinylestradiol, an ingredient of such contraceptives, has been shown to decrease serum levels of lamotrigine.[59] 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.[4]
Many studies have found no association between lamotrigine exposurein utero and birth defects, while those that have found an association have found only slight associations with minor malformations such ascleft palates.[60] Review studies have found that overall rates of congenital malformations in infants exposed to lamotriginein utero are relatively low (1–4%), which is similar to the rate of malformations in the general population.[61][62] It is known that lamotrigine is a weak inhibitor of humandihydrofolate reductase (DHFR) and other, more powerful, human DHFR inhibitors such asmethotrexate are known to beteratogenic.[60]
Lamotrigine is expressed inbreast milk; the manufacturer recommends carefully weighing the benefits and risks of taking lamotrigine whilebreastfeeding.[63] However, some studies suggest that lamotrigine is safe to use while breastfeeding.[64] A frequently updated review of scientific literature rates lamotrigine as L3: moderately safe.[65]
Lamotrigine binds tomelanin-containing tissues such as the iris of the eye or melanin-rich skin. The long-term consequences of this are unknown.[66]
Lamotrigine is known to affect sleep. Studies with small numbers of patients (10–15) reported that lamotrigine increases the duration ofREM sleep, decreases the number of phase shifts, and decreases the duration ofslow-wave sleep,[67] and that there was no effect onvigilance,[68] daytime somnolence and cognitive function.[69] However, a retrospective study of 109 patients' medical records found that 6.7% of patients experienced an "alerting effect" resulting in intolerableinsomnia, for which the treatment had to be discontinued.[70]
Lamotrigine can induce a type of seizure known as amyoclonic jerk, which tends to happen soon after the use of the medication.[71] When used in the treatment of myoclonic epilepsies such asjuvenile 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 intostatus epilepticus, which is a medical emergency. It can also cause myoclonic status epilepticus.[4]
In overdose, lamotrigine can cause uncontrolled seizures in most people. Reported results in overdoses involving up to 15 g include increased seizures, coma, and death.[4]
Lamotrigine is a member of thesodium channel blocking class of antiepileptic drugs.[72] This may suppress the release ofglutamate andaspartate, two dominant excitatory neurotransmitters in the central nervous system.[4] It is generally accepted to be a member of the sodium channel blocking class ofantiepileptic drugs,[73] but it could have additional actions, since it has a broader spectrum of action than other sodium channel antiepileptic drugs such asphenytoin 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 itssigma receptor activity. In addition, lamotrigine shares few side effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties.[74]
Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors that anticonvulsants affect (adrenergic,dopamineD1 andD2,muscarinic,GABA,histaminergicH1,serotonin5-HT2, andN-methyl-D-aspartate). Inhibitory effects on5-HT,norepinephrine, and dopamine transporters are weak. According to the article, the IC50 values are 240μM (5-HT, human platelets), 474 μM (5-HT, rat brain synaptosomes), 239 μM (norepinephrine) and 322 μM (dopamine).[80] Lamotrigine blocks NMDA receptor-initiatedarachidonic acid signalling in rat brain.[81] Lamotrigine is a weak inhibitor ofdihydrofolate reductase,[4] 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 slicesin vitro. As is the case for antiepileptic drugs that act on voltage-dependent sodium channels, lamotrigine thereby inhibits the release ofglutamate andaspartate, which is evoked by the sodium-channel activatorveratrine and was less effective in the inhibition ofacetylcholine orGABA release. At high concentrations, it did not affect spontaneous orpotassium-evoked amino acid release.[4]
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 andcarbamazepine, 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 generalizedabsence 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 onvoltage-gated calcium channels. Lamotrigine blocks T-typecalcium 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.
Thepharmacokinetics of lamotrigine followfirst-order kinetics, with ahalf-life of 29 hours and volume of distribution of 1.36L/kg.[82] Lamotrigine is rapidly and completely absorbed after oral administration. Its absolutebioavailability is 98% and its plasmaCmax 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 1.3L/kg. This is independent of dose and is similar to following single and multiple doses in both patients with epilepsy and in healthy volunteers.[83]
Lamotrigine has fewer drug interactions than manyanticonvulsant drugs, although pharmacokinetic interactions withcarbamazepine,phenytoin and other hepatic enzyme-inducing medications may shortenhalf-life.[86] Dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance.[4]
The capacity of available tests to detect potentially adverse consequences ofmelanin 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.[4]
1980 — initial patent filings are made by the Wellcome Foundation.[87]
1990 — lamotrigine is approved for use in Ireland to treat epilepsy.[12]
1991 — lamotrigine is used in the United Kingdom as an anticonvulsant medication[90]
December 1994 — lamotrigine was approved for use in the United States for the treatment ofpartial seizures.[91]
August 1998 — for use as adjunctive treatment ofLennox-Gastaut syndrome in pediatric and adult patients, new dosage form: chewable dispersible tablets.[citation needed]
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]
January 2003 — for use as adjunctive therapy for partial seizures in pediatric patients as young as two years of age.
January 2004 — for use as monotherapy for the treatment of partial seizures in adult patients when converting from the anti-epileptic drugvalproate (includingvalproic acid)[citation needed]
In March 2021, the United States Food and Drug Administration (FDA) issued a warning regarding the potential forcardiac arrhythmias in people with pre-existing structural or conduction heart defects.[93][94] The warning provoked consternation and controversy within the professional community.[95] Anin vitro study conducted in 2011 predicted Class IB antiarrhythmic activity at therapeutic concentrations of lamotrigine, due to its sodium channel-blocking activity.[96] 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.[93] A rapid systematic review concluded that "there is insufficient evidence to support or refute that lamotrigine is associated with sudden death or electrocardiogram changes..."[97] The FDA has recommended that further studies are conducted with lamotrigine and other sodium-channel blocking antiseizure medications.[94]
In March 2023, anFDA Adverse Event Reporting System analysis demonstrated signals ofcardiac arrest, but not oftachyarrhythmia orbradyarrhythmia 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 onoverdose andsuicide 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.[98]
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.[99]
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