Lamotrigine

Lamotrigine is a novel anticonvulsant drug for inhibition of 5-HT with IC50 of 240 μM and 474 μM in human platelets and rat brain synaptosomes, and also is a sodium channel blocker.

Lamotrigine-related pseudolymphoma presenting as cervical lymphadenopathy.[Pubmed:28348962]

Epilepsy Behav Case Rep. 2017 Jan 18;7:40-41.

Immune-mediated drug reactions are a potentially life-threatening complication of antiseizure medications. Drug hypersensitivity syndrome (DHS) is the best recognised of these, presenting with fever, eosinophilia, rash and internal organ involvement. Isolated lymphadenopathy is a less recognized immune-mediated reaction to antiseizure drugs such as Lamotrigine. We describe the case of a 24-year-old woman who developed Lamotrigine-related bilateral cervical lymphadenopathy (pseudolymphoma) fifteen months following therapy initiation. This is the second such case reported in the medical literature.

Long-term efficacy and safety of lamotrigine for all types of bipolar disorder.[Pubmed:28360522]

Neuropsychiatr Dis Treat. 2017 Mar 20;13:843-854.

BACKGROUND: We investigated whether the long-term efficacy and safety of Lamotrigine (LTG) for bipolar disorder (BP) differs between disease types (BP-I, BP-II, or BP not otherwise specified [BP-NOS]), and the efficacy of the concomitant use of antidepressants (ADs). METHODS: For >1 year, we observed 445 outpatients with BP (diagnosed by DSM-IV criteria) who initiated LTG treatment between July 1 and October 31, 2011, using the Himorogi Self-rating Depression (HSDS) and Anxiety Scales and the Clinical Global Impression-Improvement scale and also recorded adverse events. RESULTS: Treatment efficacy was observed at week 4, with the improved HSDS scores sustained until week 52 for all types of BP; 50% of the patients with any type of BP could be treated with LTG for 1 year, whereas ~40% could be treated for >1.5 years. However, 25% of the patients were withdrawn within the first 4 weeks. The overall incidence of adverse events was 22.9% (104/455): 34.1% (14/41) for BP-I, 22.7% (15/66) for BP-II, and 22.2% (75/338) for BP-NOS. The most common adverse event was skin rash: 22.0% for BP-I, 16.7% for BP-II, and 12.1% for BP-NOS. LIMITATIONS: There was no control group. Data were collected retrospectively. CONCLUSION: With careful and adequate titration, long-term treatment with LTG is possible for any type of BP, with BP-NOS patients, the largest population in clinical practice, responding particularly well. Symptoms can improve with or without ADs. Large-scale prospective studies of the efficacy of ADs in bipolar treatment are warranted.

The anticonvulsive drug lamotrigine blocks neuronal {alpha}4{beta}2 nicotinic acetylcholine receptors.[Pubmed:20688974]

J Pharmacol Exp Ther. 2010 Nov;335(2):401-8.

Lamotrigine (LTG), an anticonvulsive drug, is often used for the treatment of a variety of epilepsies. In addition to block of sodium channels, LTG may act on other targets to exert its antiepileptic effect. In the present study, we evaluated the effects of LTG on neuronal nicotinic acetylcholine receptors (nAChRs) using the patch-clamp technique on human alpha4beta2-nAChRs heterologously expressed in the SH-EP1 cell line and on native alpha4beta2-nAChRs in dopaminergic (DA) neurons in rat ventral tegmental area (VTA). In SH-EP1 cells, LTG diminished the peak and steady-state components of the inward alpha4beta2-nAChR-mediated currents. This effect exhibited concentration-, voltage- and use-dependent behavior. Nicotine dose-response curves showed that in the presence of LTG, the nicotine-induced maximal current was reduced, suggesting a noncompetitive inhibition. These findings suggest that LTG inhibits human neuronal alpha4beta2-nAChR function through an open-channel blocking mechanism. LTG-induced inhibition in alpha4beta2-nAChRs was more profound when preceded by a 2-min pretreatment, after which the nicotine-induced current was reduced even without coapplication of LTG, suggesting that LTG is also able to inhibit alpha4beta2-nAChRs without channel activation. In freshly dissociated VTA DA neurons, LTG inhibited alpha4beta2-nAChR-mediated currents but did not affect glutamate- or GABA-induced currents, indicating that LTG selectively inhibits nAChR function. Collectively, our data suggest that the neuronal alpha4beta2-nAChR is likely an important target for mediating the anticonvulsive effect of LTG and the blockade of alpha4beta2-nAChR possibly underlying the mechanism through which LTG effectively controls some types of epilepsy, such as autosomal dominant nocturnal frontal lobe epilepsy or juvenile myoclonic epilepsy.

Modulation of calcium and potassium currents by lamotrigine.[Pubmed:9778600]

Neuropsychobiology. 1998 Oct;38(3):131-8.

Actions of the new antiepileptic drug Lamotrigine (LTG) were characterized using extracellular and whole cell patch clamp recordings from rat CA1 and CA3 pyramidal cells in vitro. The results suggest that LTG, beside its previously described effect on the fast sodium inward current, also modulates - presumably voltage-gated - calcium currents and the transient potassium outward current ID. These may be effective mechanisms to inhibit pathological excitation in epilepsy and may be of potential benefit in treating underlying cellular disturbances in bipolar disorder.

Lamotrigine reduces voltage-gated sodium currents in rat central neurons in culture.[Pubmed:9184596]

Epilepsia. 1997 May;38(5):522-5.

PURPOSE: To study the mechanism or mechanisms of action of Lamotrigine (LTG) and, in particular, to establish its effects on the function of NA+ channels in mammalian central neurons. METHODS: Rat cerebellar granule cells in culture were subjected to the whole-cell mode of voltage clamping under experimental conditions designed to study voltage-gated Na+ currents. RESULTS: Extracellular application of LTG (10-500 microM, n = 21) decreased in a dose-related manner a tetrodotoxin-sensitive inward current that was elicited by depolarizing commands (from -80 to +20 mV). The peak amplitude of this Na(+)-mediated current was diminished by 38.8 +/- 12.2% (mean +/- SD, n = 6) during application of 100 microM LTG, and the dose-response curve of this effect indicated an IC50 of 145 microM. The reduction in the inward currents produced by LTG was not associate with any significant change in the current decay, whereas the voltage dependency of the steady-state inactivation shifted toward more negative values (midpoint of the inactivation curve: -47.5 and -59.0 mV under control conditions and during application of 100 microM LTG, respectively, n = 4). CONCLUSIONS: Our findings indicate that LTG reduces the amplitude of voltage-gated Na+ inward current in rat cerebellar granule cells and induces a negative shift of the steady-state inactivation curve. Both mechanisms may be instrumental in controlling the repetitive firing of action potentials (AP) that occurs in neuronal networks during seizure activity.

Neurochemical and behavioral aspects of lamotrigine.[Pubmed:1685439]

Epilepsia. 1991;32 Suppl 2:S4-8.

Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 micrograms/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 micrograms/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP-like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic brain damage.

Lamotrigine(BW430C) is a novel anticonvulsant drug for inhibition of 5-HT and sodium channel Target: Sodium Channel Lamotrigine stabilises presynaptic neuronal membranes by blockade of voltage-dependent sodium channels, thus preventing the release of excitatory neurotransmitters, particularly glutamate and aspartate [1].

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