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lamotrigine
Lamotrigine, sold as the brand name Lamictal among others, is an anticonvulsant medication used to treat epilepsy and bipolar disorder.[2] For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome.[2] In bipolar disorder, it is used to treat acute episodes of depression, rapid cycling in bipolar type II, and prevent recurrence in bipolar type I.[2]
Common side effects include sleepiness, headache, vomiting, trouble with coordination, and rash.[2] Serious side effects include lack of red blood cells, increased risk of suicide, Stevens-Johnson syndrome, and allergic reactions.[2] There are concerns that use during pregnancy or breastfeeding may result in harm.[3] Lamotrigine is a phenyltriazine, making it chemically different from other anticonvulsants.[2] How it works is not exactly clear.[2] It appears to increase the action of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system and decrease voltage-sensitive sodium channels.[2][4]
Lamotrigine was first marketed in the United Kingdom in 1991 and approved for use in the United States in 1994.[2][5] It is on the World Health Organization's List of Essential Medicines, the most effective and safest medicines needed in a health system.[6] The wholesale cost in the developing world is about 3.57 USD per month as of 2015.[7] In the United States, this amount has a wholesale cost of about 4.64 USD.[8]
Medical uses
Epilepsy
Lamotrigine is used for the treatment of partial seizures.[9] It is considered a first-line drug for primary generalised tonic-clonic seizures (includes simple partial, complex partial and secondarily generalised seizures), and as an adjuvant therapy in partial seizures (focal onset tonic-clonic, atypical absence, myoclonic, and due to Lennox-Gastaut syndrome). It is also used as an alternative medication for absence seizure and atypical absence, myoclonic, and atonic seizures.[10][11]
It is also appropriate for the treatment of Lennox–Gastaut syndrome.[12] It is one of a small number of FDA-approved therapies for this severe form of epilepsy. Lamotrigine reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks.[13] Combination with valproate is common, but this increases the risk of lamotrigine-induced rash, and necessitates reduced dosing due to the interaction of these drugs.[14]
Bipolar disorder
Lamotrigine is approved in the US for maintenance treatment of bipolar I disorder and bipolar II disorder.[15][16] While the anticonvulsants carbamazepine and valproate are predominantly antimanics, lamotrigine is most effective for preventing the 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; however, it is effective at prevention of or delaying of manic, depressive, or rapid cycling episodes.[17]According to studies in 2007, lamotrigine may treat bipolar depression without triggering mania, hypomania, mixed states, or rapid-cycling.[18]
There is less evidence of therapeutic benefit when lamotrigine is used to treat a current mood episode. It has not demonstrated effectiveness in treating acute mania,[19] and there is controversy regarding the drug's effectiveness in treating acute bipolar depression.[20] While the 2002 American Psychiatric Association (APA) guidelines recommend lamotrigine as a first-line treatment for acute depression in bipolar II disorder,[21] their website notes that the guidelines, being more than five years old, "can no longer be assumed to be current".[22] A paper written in 2008 by Nasser 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".[17] A 2008 paper by Calabrese et al. examined much of the same data, and found that in five placebo-controlled studies, lamotrigine did not significantly differ from placebo in the treatment of bipolar depression.[23] However, in a meta-analysis of these studies conducted in 2008, Calabrese found that lamotrigine was effective in individuals with bipolar depression, with a number needed to treat (NNT) of 11, or 7 in severe depression.[24]
A 2013 review about lamotrigine concluded that it is recommended in bipolar maintenance when depression is prominent and that more research is needed in regard to its role in the treatment of acute bipolar depression and unipolar depression. Furthermore, no information to recommend its use in other psychiatric disorders was found.[25]
Other uses
Off-label uses include the treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, visual snow and reducing neuropathic pain,[26][27][28][29] although a systematic review conducted in 2013 concluded that well-designed clinical trials have shown no benefit for lamotrigine in neuropathic pain.[30] Off-label psychiatric usage includes the treatment of treatment-resistant obsessive-compulsive disorder,[31] depersonalization disorder,[32] hallucinogen persisting perception disorder,[33] schizoaffective disorder,[34]borderline personality disorder,[35] and post-traumatic stress disorder.[36][needs update]
Overdose
In overdose, lamotrigine can cause uncontrolled seizures in most people. Reported results in overdoses involving up to 15 grams include increased seizures, coma and death.[40]
Mechanism of action
Lamotrigine is a member of the sodium channel blocking class of antiepileptic drugs.[61] This may suppress the release of glutamate and aspartate, two of the dominant excitatory neurotransmitters in the CNS.[62] It is generally accepted to be a member of the sodium channel blocking class of antiepileptic drugs,[63] 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 emphasises its unique properties.[64]
It is a triazine derivate that inhibits voltage-sensitive sodium channels, leading to stabilization of neuronal membranes. It also blocks L-, N-, and P-type calcium channels and has weak 5-hydroxytryptamine-3 (5-HT3) receptor inhibition. These actions are thought to inhibit release of glutamate at cortical projections in the ventral striatum limbic areas,[65] and its neuroprotective and antiglutamatergic effects have been pointed out as promising contributors to its mood stabilizing activity.[66] Observations that lamotrigine reduced γ-aminobutyric acid (GABA) A receptor-mediated neurotransmission in rat amygdala, suggest that a GABAergic mechanism may also be involved.[67] It appears that lamotrigine does not increase GABA levels in humans.[68]
Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors that anticonvulsants effect (adrenergic, dopamineD1 and D2, muscarinic, GABA, histaminergic H1, serotonin 5-HT2, and N-methyl-D-aspartate). Inhibitory effects on 5-HT, norepinephrine, and dopamine transporters are weak.[69] Lamotrigine is a weak inhibitor of dihydrofolate reductase,[70] 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 had no effect on spontaneous or potassium evoked amino acid release.[46]
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-dependent 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 that 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 recognised to be protective against generalised absence epilepsy and other generalised epilepsy syndromes, including primary generalised 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-activated calcium channels. Lamotrigine blocks T-type calcium channels weakly, if at all. However, it does inhibit native and recombinant high-voltage–activated 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.
It antagonises the following receptors with the following IC50 values:[70]
5-HT3, IC50=18μM
σ receptors, IC50=145μM
