Lamotrigine

Overview
Lamotrigine (marketed as Lamictal by GlaxoSmithKline, called Lamictin in South Africa, למוג'ין (Lamogine) in Israel, and 라믹탈 in South Korea) is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. For epilepsy it is used to treat partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Lamotrigine also acts as a mood stabilizer. It is the first medication since lithium granted Food and Drug Administration (FDA) approval for the maintenance treatment of bipolar type I. Chemically unrelated to other anticonvulsants, lamotrigine has relatively few side-effects and does not require blood monitoring. The exact way lamotrigine works is unknown. Some think that it is a Na+ channel blocker. It is inactivated by hepatic glucuronidation.

Lamotrigine has been successful in controlling rapid cycling and mixed bipolar states in people who have not received adequate relief from lithium, carbamazepine and/or valproate, possibly having significantly more antidepressant potency than either carbamazepine or valproate. It is useful as part of the treatment of some people with major (unipolar) depression, and has recently been reported to be a useful treatment for some people with post-traumatic stress disorder (PTSD) and borderline personality disorder (BPD). (Source: Lamotragine FAQ.)

Indications and usage
The US FDA approved lamotrigine (Lamictal) for the treatment of epilepsy in 1994, and bipolar I disorder in 2003. Off-label uses include the treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reducing neuropathic pain (Backonja, 2004; Jensen 2002; Pappagallo, 2003). Off-label psychiatric usage includes the treatment of bipolar II disorders, schizoaffective disorder, borderline personality disorder, post traumatic stress disorder, and as adjunctive therapy for "treatment-resistant" unipolar depression (Barbosa, Berk & Vorster, 2003). Lamotrigine is one of a small number of FDA-approved therapies for seizures associated with Lennox-Gastaut syndrome; it is one of two approved for the maintenance treatment of bipolar disorder.

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy. Typically developing before 4 years of age, LGS is associated with developmental delays. There is no cure, treatment is often complicated, and complete recovery is rare. Symptoms include the atonic seizure (also known as a "drop attack"), during which brief loss of muscle tone and consciousness cause abrupt falls. Lamotrigine significantly reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks (French et al., 2004). 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 (Pellock, 1999).

Lamotrigine (Lamictal) is the first FDA-approved therapy since lithium for maintenance treatment of bipolar I disorder (GlaxoSmithKline, 2003). While traditional anticonvulsant drugs are primarily antimanics, lamotrigine is most effective in the treatment and prophylaxis of bipolar depression. Lamotrigine treats bipolar depression without triggering mania, hypomania, mixed states, or rapid-cycling, and the 2002 American Psychiatric Association guidelines recommended lamotrigine as a first-line treatment for acute depression in bipolar disorder as well as a maintenance therapy, however lamotrigine is not indicated "on label" for treatment of acute symptoms.

Dosing
The pharmacokinetics of lamotrigine are quite complicated, with highly varying half-life and blood plasma levels. Thus, therapeutic plasma concentrations of lamotrigine are unknown, and according to the manufacturer, dosing should be based on therapeutic response. Lamotrigine is sometimes used in combination with other psychiatric drugs, such as members of the valproate family, and this interaction also can radically affect appropriate dosages. Together these factors make the dosage schedule (the amount which is appropriate to take) among the most complex of all psychiatric medicines.

Lamotrigine dosages are generally increased and decreased relatively gradually. A therapeutic response may require weeks or months of subsequent dose escalations, and very small differences in dosage often have noticeably different effects, much more so than with most other psychiatric medications; as little as 10% more or less may make a noticeable difference.

In addition to closely monitoring therapeutic responses, the conservative titration minimizes the risk of inducing the potentially life-threatening (but rare) Stevens-Johnson syndrome rash. Dosing should be reduced gradually as well, as abrupt discontinuation of any anticonvulsant increases the risk of seizures, even without a history of epilepsy.

GlaxoSmithKline's trademarked brand of Lamotrigine, Lamictal, is manufactured in scored tablets (25 mg, 100 mg, 150 mg and 200 mg) and chewable dispersible tablets (2 mg, 5 mg and 25 mg). Five-week sample kits are also available; these include titration instructions and scored tablets (25 mg for patients taking valproate, 25 mg and 100 mg for patients not taking valproate). Lamotrigine is also available in un-scored tablet form. In 2005, Teva Pharmaceutical Industries Ltd. began selling generic Lamotrigine in the United States, but only in 5 mg and 25 mg chewable dispersible tablets. Lamotrigine is also available in generic form in the United Kingdom and Canada.

Bipolar and depression dosages
The recommended initial dosing begins at 25 mg for bipolar disorder, though some have recommended starting at half of that. Antidepressant effects have been reported at as little as 25 mg per day, but typically begin at 100 mg a day, and mood stabilization takes place between 100 mg to 200 mg a day.

These numbers may be as much as halved for those also taking valproate family antiepileptic drugs, which inhibit the metabolism of lamotrigine, more than doubling its half-life and require that a lower dose of lamotrigine be used. The numbers may be as much as doubled for those taking enzyme-inducing anti-epileptic drugs (including carbamazepine USP (Tegretol); oxcarbazepine (Trileptal); and phenytoin (Dilantin)), which enhance the metabolism of lamotrigine (causing it to be broken down more quickly), and its dosage must be increased when taken with these drugs; the same consideration is required when Lamictal is taken with hormonal contraception.

Those taking Lamotrigine in combination with a valproate are instructed to take the daily amount of medication all at once, while those taking the enzyme-inducing anti-convulsants are instructed to split the daily amount into two doses. Those taking neither of the other two classes of drugs usually take the entire daily amount as a single dose.

Clinical studies show no effective difference for depression or bipolar disorder beyond 200 mg, however antimanic effects may not begin until doses of 400 mg a day, and some bipolar patients report feeling useful effects above the 200 mg per day level. GlaxoSmithKline suggests maintenance doses up to 400 mg for bipolar disorder, unless the patient is taking a valproate, in which case a maximum of 200 mg is suggested.

Epilepsy dosages
Due to the numerous types of epilepsy and drug interaction complications, dosages for epilepsy can be even more complex than those for bipolar disorders; advice from qualified medical professionals is essential.

The recommended initial dosing begins at less than 1 mg for epilepsy. Generally, the therapeutic range for epilepsy is 300 mg to 500 mg a day, unless the patient is also taking a valproate drug, in which case it is normally 100 mg to 200 mg per day.

Side effects
Lamotrigine prescribing information has a black box warning about life threatening skin reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. The manufacturer states that nearly all cases appear in the first 2 to 8 weeks of therapy and if medication is suddenly stopped then resumed at the normal dosage. Patients should seek medical attention for any unexpected skin rash as its presence is an indication of a deadly side effect of the drug.

Cognitive side effects are common with doses over 50mg qid, per 2001-2003 Glaxo-sponsored Clinical Trials comparing quality of life between Topiramate and Lamotigine in healthy volunteers (unpublished). Common side effects include headaches, dizziness and insomnia. Other side effects may include acne and skin irritation, vivid dreams or nightmares, night sweats, body aches and cramps, fatigue, memory and cognitive problems, irritability, weight changes, hair loss, changes in libido, frequent urination, nausea, and other side effects. In very rare cases, Lamotrigine has been known to cause the development of a dangerous rash called Stevens-Johnson syndrome (or SJS). The rash is more common in children, so this medication is often reserved for adults. There is also an increased incidence of this rash in patients who are currently on, or recently discontinued a valproates anti-convulsant drug, as these medications interact in such a way that the clearance of both is decreased and the effective dose of lamotrigine is increased. Muscle aches are another fairly common side effect, and there are occasional reports of dry mouth.

In clinical trials women were more likely than men to have side effects. This is the opposite of most other anticonvulsants and antipsychotics. It's been suggested that genetic background makes a difference in dosages, with those of non-Caucasian background typically needing lower doses.

Lamotrigine binds to melanin-containing tissues such as the iris of the eye. The long-term consequences of this are unknown.

Use during pregnancy is recommended only if benefits outweigh potential risks. It was also reported on CNN in September 2006 that taking Lamictal during the first trimester of pregnancy can lead to a cleft palate in babies. Lamotrigine is found in breast milk; breast-feeding is not recommended during treatment.

Some patients have reported experiencing a loss of concentration, even with very small doses, while some others have actually reported an increase in alertness and concentration. In general, however, it tends to have less of an impact on concentration relative to other mood stabilizers. GlaxoSmithKline investigated lamotrigine for the treatment of ADHD. The results were inconclusive. No detrimental effects on cognitive function were observed, however, the only statistical improvement in core ADHD symptoms was an improvement on a test (PASAT) that measures auditory processing speed and calculation ability.

Mechanism of action
One proposed mechanism of action for lamotrigine involves an effect on sodium channels, although this remains to be established in humans. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g. glutamate and aspartate).

U.S. FDA approval history

 * December 1994 - for use as adjunctive treatment for partial seizures with or without secondary generalization in adult patients (16 years of age and older).
 * August 1998 - for use as adjunctive treatment of Lennox-Gastaut syndrome in pediatric and adult patients, new dosage form: chewable dispersible tablets.
 * December 1998 - for use as monotherapy for treatment of partial seizures in adult patients when converting from a single enzyme-inducing anti-epileptic drug (EIAED).
 * January 2003 - for use as adjunctive therapy for partial seizures in pediatric patients as young as 2 years of age.
 * June 2003 - for the maintenance treatment of adults with Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. Additionally, the FDA has noted that findings for Lamictal maintenance treatment were more robust in bipolar depression.
 * January 2004 - for use as monotherapy for treatment of partial seizures in adult patients when converting from the anti-epileptic drug valproate (including valproic acid (Depakene) and divalproex sodium (Depakote)).