Lamictal: clinical uses and mechanisms of action

Lamictal: The Oral Anticonvulsant and Antidepressant

Lamictal is an anticonvulsant and antidepressant for the treatment of epilepsy and other mood disorders (Thase and Denko,2008).Its generic name is lamotrigine. Lamictal is an oral anticonvulsant agent that was developed on the basis of the observation that certain antiepileptic drugs can initiate antifolate activity. The drug is derived from certain agents that have an inhibition of dihydrofolate reductase.Lamictal however, has very limited antifolate activity. As a consequence of possible rashes that are life-threatening that include Stevens-Johnson syndrome as well as epidermal neclysis which is toxic, lamictal has a boxed warning that states that its administration should be discontinued should rashes appear at any stage of its administration. The only factor that is currently known to effectively predict the severity as well as occurrence of the rashes is age. Pediatric patients have also been shown to be at increased risk. Lamictal has been indicated to be a highly effective anticonvulsant and administered as an adjunctive treatment for various types of refractory partial seizures. This is for seizures having or not having tonic-clonic seizures that are not generalized. It may be administered to adults for the treatment of partial seizures in patients on monotherapy with an antiepileptic drug that is enzyme-inducing. Lamictal has been noted to result in an improvement in the quality of life as compared to the administration of placebo. Patients have been noted to experience an improvement in the level of seizure severity, happiness as well as mastery as pointed out by Goa, Ross and Chrisp (1993).

FDA approval

FDA originally approved Lamictal in December of 1994. Motte et al. (1997) pointed out that Lamictal is effective in the treatment and management of Lennox-Gastaut syndrome.FDA approved Lamictal for the use in both pediatric as well as adult patients in 1998.In 1998, FDA approved a chewable Lamictal tablet. In January of 2003, FDA then approved Lamictal tablet as an adjunctive therapy for use in the treatment of partial seizures in children of two or more than two years. January 2003 saw the approval of Lamictal for the monotherapy treatment of patients of sixteen years or older. This only applies when changing from valpoate therapy.In June 2003,FDA approved FDA for the long-term treatment of the mental condition called bipolar I disorder. September 2006 saw the approval of Lamictal for use in adjunct therapy in the management and treatment of primary generalized tonic-clonic seizures.May 2009 saw the approval of the orally disintegrating tablet (ODT) formulation. In June 2009,Lamictal XR which is an extended formulation of the drug for use in patients of 13 years or older was approved by FDA as an adjunctive therapy for the onset of partial seizures having or not having secondary generalization. In February 2010, FDA approved Lamictal as an adjunctive therapy for the treatment of primary generalized tonic-clonic seizures.In April 2011, an extended-release Lamictal was approved by FDA for use on conversion to monotherapy in 13 years old or older patients having partial the safety as well as the efficacy of the extended-release Lamictal has never been established as a simultaneous or initial monotherapy conversion to monotherapy from a two or more AED concomitants.Lamictal has in the past been administered to patients suffering from bipolar disorder especially acute mania.

Lamictal has been approved for both labeled use and unlabeled .The in labeled uses of the drug includes its use in the treatment and management of cyclothymia, which is a mild form of bipolar disorder, the treatment of unipolar depression as well as schizoaffective disorder.Lamictal can also be used for the treatment of borderline personality disorder. When Lamictal is administered with other anticonvulsants in the treatment of mood disorders, then they are considered to be mood stabilizers. A series of clinical studies have shown that Lamictal is extremely effective in the treatment of depressed as well as cyclic bipolar disorder (Keck and McElroy,2003).This is especially true for patients who have partial or totally lack any response to lithium administration. The drug can either be administered alone or in combination with other mood stabilizers such as lithium. When administered with Depakote, some precautions must be taken in order to reduce the risks of developing severe rash.

Mechanism of action

The exact mechanism of action that Lamictal takes is not known (GlaxoSmithKline,2004). Several studies however, seems to suggest that Lamictal acts by stabilizing the neuronal membranes through the actions that target the sodium channels that are voltage sensitive. The blockage of the sodium channels then leads to a reduction in the level of presynaptic release of aspartate and glutamate which subsequently leads to the decrease in the frequency of seizures. The mechanism has been noted to be similar to that of phenytoin and cabamazepine. Lamictal has very limited or no effect at all on the release of dopamine, GABA, norepinephrine or acetylcholine. Lamictal is a very weak inhibitor of dihydrofolate reductase in vitro as well as in animal studies. There is not effect of Lamictal on folate in all clinical studies. There is a however a possibility that the concentration of folate may decrease in the process of gestation.

Dosage

Certain medication errors have been reported with Lamictal starter kits. Dosage errors usually lead to mild and severe side effects such as Stevens - Johnson syndrome. There are three different starter kits each bearing different titration schedules. To avoid under dosing or overdosing, patients must receive the appropriate kit. These are

Orange starter kits: These are for patients who are not taking phenytion, carbamazepine, valporate, primidone or rifampin.

Green starter kits:These are for patients who are taking phenytion, carbamazepine, primidone or rifampin and not taking valporate.

Blue starter kits: These are specifically for patients who are taking valpoate.

The dosage of Lamictal is usually started at a rather low dosage of about 25 mg/day. This dosage is then increased gradually by 25 to 50 mg every two weeks. During the 6th week, most patients are already taking a dosage of 100 to 200mg/day.When the drug is administered together with Depakote, the dosage should be a little bit slower (about 25 mg every day for he initial two weeks) .The ideal dosage should not be more that 100 mg/day. However, when administered with carbamazepine (Tegretol) the dosage may be adjusted to be higher since carbamazepine accelerates its metabolism. GlaxoSmithKline (2011) pointed out that the safety as wells the effectiveness of the extended-release Lamictal tablets have not yet been determined.

The Common side effects

The side effects that are associated with the administration of Lamictal are dizziness, rashes, impaired coordination, headache as well as ataxia (difficulty in walking).gastrointestinal symptoms have also been noted to occur. These include abdominal cramping, vomiting and nausea. The occurrence of rashes as a result of Lamictal administration is approximated to be about ten percent (GlaxoSmithKline,2004).This risk however, may be increased significantly should the dosage be too rapid or be in combination with the drug Depakote and any other derivatives of valporates.

Adverse reactions as well as precautions

Lamictal has been noted to result in impaired alertness and drowsiness at the beginning of the therapy. It is therefore important for patients to practice caution when driving or taking part in activities that require a high degree of alertness. Due to the risk of developing life threatening rashes, FDA requires the manufacturers to a warning (black box ) on its labeling. The risks of developing the skin reaction is approximated to be one for every a thousand patients I adults. This risk is however higher in children with one in every one hundred patients who are under sixteen years old. The life threatening rashes known as Stevens-Johnson syndrome is characterized by the appearance of painful blisters to the skin as well as the mucous membrane. This condition is often fatal. The skin reaction occurs on the basis of the susceptibility of a given individual. As pointed out earlier, age is the only factor that can be used in the prediction of a person's susceptibility to Stevens-Johnson syndrome. GlaxoSmithKline (2004) pointed out that the administration of Lamictal should be discontinued at the first sigh of the rashes. Immediate medical attention should be sort should the rashes be accompanied by fever, malaise and sore throat.