Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder.
[18][19] 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.
[20] 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.
[20] Evidence supporting the use of lamotrigine as an add-on therapy for drug-resistant focal epilepsy found that it is likely effective for reducing seizure frequency and is generally well tolerated.
[23] Combination with valproate is common, but this increases the risk of lamotrigine-induced severe skin reaction Stevens–Johnson syndrome, and necessitates reduced dosing due to the interaction of these drugs.
[25] While the anticonvulsants carbamazepine and valproate are predominantly antimanics, lamotrigine has demonstrated efficacy only in preventing or reducing the risk of recurrent depressive episodes of bipolar disorder.
[29] 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 reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines, and it concludes that lamotrigine has "very limited, if any, efficacy in the treatment of acute bipolar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".
[26] 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.
However, various publications[33][34] and textbooks[35][36] have expressed that lamotrigine could be added to clozapine as augmentation therapy against partial or non-responding patients with schizophrenia.
[37] Off-label uses include the treatment of major depressive disorder, peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, visual snow, and reducing neuropathic pain from any cause,[38][39][40][41] although a systematic review conducted in 2013 concluded that well-designed clinical trials have shown no benefit for lamotrigine in neuropathic pain.
[49] Another study reported that lamotrigine might be a safe and effective treatment option for adult ADHD comorbid with bipolar and recurrent depression.
[50] Side effects such as rash, fever, and fatigue are very serious, as they may indicate incipient SJS, TEN, DRESS syndrome, or aseptic meningitis.
[5] 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.
[53] Other side effects include alopecia (hair loss), loss of balance or coordination, double vision, crossed eyes, pupil constriction, blurred vision, dizziness and lack of coordination, drowsiness, insomnia, anxiety, vivid dreams or nightmares, dry mouth, mouth ulcers, memory problems, mood changes, itchiness, runny nose, cough, nausea, indigestion, abdominal pain, weight loss, missed or painful menstrual periods, and vaginitis.
[58] Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy.
In addition, lamotrigine shares few side effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties.
[74] These actions are thought to inhibit release of glutamate at cortical projections in the ventral striatum limbic areas,[75] and its neuroprotective and antiglutamatergic effects have been pointed out as promising contributors to its mood stabilizing activity.
[76] Observations that lamotrigine reduced GABAA receptor-mediated neurotransmission in rat amygdala suggest that a GABAergic mechanism may also be involved.
[78] Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors that anticonvulsants affect (adrenergic, dopamine D1 and D2, muscarinic, GABA, histaminergic H1, serotonin 5-HT2, and N-methyl-D-aspartate).
[79] Lamotrigine is a weak inhibitor of dihydrofolate reductase,[5] 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.
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.
The basis for this broader spectrum of activity of lamotrigine is unknown but could relate to actions of the drug on voltage-gated calcium channels.
Patient compliance should be periodically reassessed with lab and medical testing of liver and kidney function to monitor progress or side effects.
In March 2021, the United States Food and Drug Administration (FDA) issued a warning regarding the potential for cardiac arrhythmias in people with pre-existing structural or conduction heart defects.
[94] 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.
[92]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.