Focus on Lamotrigine Ivan Goldberg, M.D. 1346 Lexington Avenue New York, NY 10128 Voice: + 212 876 7800 Fax: + 212 737 0473

Lamotrigine is currently available in about 60 countries. The drug is currently only approved for the treatment of people with seizures. There are no systematic studies that establish the safety or efficacy of lamotrigine as a treatment for people with mood disorders.While such studies are in the planning stages, what is currently known about the use of lamotrigine for the control of mood disorders comes from uncontrolled casereports.

Introduction

Lamotrigine is an anticonvulsant that is chemically unrelated to any other anticonvulsant or mood regulating medication.Lamotrigine received final approval for marketing in the USDA on 27 December 1994 and is labeled for use as an anticonvulsant. It has full patent protection and a generic version is not available yet.

The two major differences between lamotrigine and other mood
regulating drugs are:

• Lamotrigine's frequent effectiveness for patients
  who have failed to respond to antidepressants or
  mood stabilizers;
• Lamotrigine's relatively benign side-effect profile
  
  

Lamotrigine has had been successful in controlling rapid cycling and mixed bipolar states in people who have not received adequate relief from carbamazepine and/or valproate.It also appears that lamotrigine has significantly more antidepressant potency than either carbamazepine or valproate.

What sorts of mood disorders might be treated with lamotrigine?

It is too early to be very specific about which mood disorders are most likely to respond to treatment with lamotrigine. There are just about no published reports on lamotrigine's use in psychiatry. Patients with hard-to-treat bipolar syndromes seem to have been treated more often than patients with "treatment-resistant" unipolar disorders. Some people with such hard to treat unipolar depressions have been treated with good results.

The initial use of lamotrigine was to treat depressed, manic and mixed states that did not respond to existing medications. Some patients are now being maintained on lamotrigine on a long term basis in an attempt to prevent future episodes. The effectiveness of lamotrigine as a long-term prophylactic agent is currently being established.

Pre-treatment precautions

Before lamotrigine is prescribed the patient should have a thorough medical evaluation, including blood and urine tests, to rule out any medical condition, such as thyroid disorders, that may cause or exacerbate a mood disorder.

Starting treatment

In people not taking carbamazepine or valproate, lamotrigine is usually initially prescribed at an initial dose of 25 mg once or twice a day and the dose increased by 25 or 50 mg every week or two.

In people taking valproate the initial dose of lamotrigine is often 12.5 mg/day and the drug is increased by 12.5 or 25 mg every two weeks.

In people taking carbamazepine somewhat larger initial doses and more rapid increases in dose are possible.

No interaction between lithium and lamotrigine has been reported.

Carbamazepine induces enzymes that facilitate the metabolism of lamotrigine. Because of that, blood levels of lamotrigine are somewhat lower in people taking carbamazepine than in those not taking carbamazepine.

Valproate has the ability to double plasma levels of lamotrigine. because of that, when lamotrigine is started in people taking valproate, the initial dose should be approximately 50% as much as is usually initially prescribed.

When used as an antidepressant or as a mood-stabilizing agent the final dose of lamotrigine is most often between 100 and 200 mg/day. Some people require doses as high as 400 mg/day to achieve a good antidepressant effect. Such doses should avoided in patients taking valproate because of the pharmacokinetic effect of valproate that increases plasma levels of lamotrigine, and the accompanying increased risk of serious dermatological side effects.

While some people notice the antimanic and antidepressant effects early in treatment, others have to take a therapeutic amount of lamotrigine for up to a month before being aware of a significant amount of improvement.

Side effects and risks

Here is a listing of lamotrigine's side effects that affected 10% or more of the 711 people taking the drug during clinical trials and the frequency of those side effects in the 419 people treated with placebo in those trials:

Side-effects are most noticeable the few days after an increase in dose and then usually fade.

The side-effect of lamotrigine that most often causes the drug to be discontinued is a rash. Rashes can be mild, similar to a slight sunburn, or can be quite severe resembling a severe case of poison-ivy. The more severe the rash the less likely it is that the individual will be able to continue the medication. ALL rashes should be reported to the physicians prescribing the lamotrigine.

A rash is more likely to develop when the initial doses of lamotrigine are high or when lamotrigine is too rapidly started when someone is taking valproate.

Not everyone who develops a rash wile taking lamotrigine goes on to discontinue the drug, and some people with rashes go on to have a good clinical response to continued therapy.

Psychiatric side effects

Among the rarely reported side effects of lamotrigine are agitation, anxiety, concentration problems, confusion, depression, emotional lability, irritability, and mania.

Interactions

Only a few interactions between lamotrigine and other drugs have been identified. Lamotrigine increases the plasma level of carbamazepine and its metabolites. Carbamazepine lowers the concentration of lamotrigine in the blood.

Valproate doubles the plasma level of lamotrigine, and the level of valproate is decreased by about 25% in people taking lamotrigine.

Phenobarbital and primidone lower the plasma level of lamotrigine by about 40%.

Interactions with other prescription and over-the-counter drugs
are not known at this time.

Alcohol may increase the severity of the side-effects of lamotrigine.

Safety in Pregancy and Childhood

Lamotrigine is has been placed in the FDA pregnancy Category C:

"Animal studies have shown an adverse effect on the fetus but there are no adequate studies in humans; The benefits from the use of the drug in pregnant women may be acceptable despite its potential risks . . . ."

While lamotrigine has been safely used with children and young adolescents in other countries. In the USA lamotrigine is only approved for use in those over the age of 16

Discontinuing the drug

There are no specific symptoms that have been described following the abrupt discontinuation of lamotrigine, other than the seizures that sometimes follow the rapid discontinuation of any anticonvulsant. Only when necessary because of a serious side effect, should lamotrigine be suddenly discontinued.

Safety in Overdose

Data on overdoses are scarce. Two individuals who took over
4,000 mg of lamotrigine survived without sequelae.

Cost issues

As of 3 October 1996, 100 tablets of lamotrigine, when ordered from a well-known mail-order pharmacy in the USA cost:

Conclusions

Lamotrigine seems to be effective in about two-thirds of people with bipolar mood disorders that have not responded to lithium or other mood-stabilizers. Some people who have not been able to tolerate any antidepressant because of switches to mania or increased speed or intensity of
cycling, or because of the development of mixed states, have been able to tolerate therapeutic doses of anti-depressants when taking lamotrigine.

As lamotrigine has only been available for a relatively short time, (it was first marketed in 1990), there is no information about long term side-effects. As its use with people with mood disorders started even more recently, it is not known is people who initially do well on lamotrigine continue to do so after many years of treatment.

There are two major reasons why physicians prescribe and patients take lamotrigine rather than conventional, better established drugs. They are that not everyone benefits from treatment with the older, better known drugs, and that some patients find the side effects of the established drugs to be unacceptable.

References

Smith RM Lamotrigine in treatment-refractory bipolar disorder.
http://www.medscape/APA/APA-05.07.96/APA13-5.7.96.html

Calabrese JR Fatemi SH Woyshville MJ Antidepressant effects of lamotrigine
in rapid-cycling bipolar disorder. American Journal of Psychiatry 1996, 53
(9), 1236.