A Clinician's Approach to Anticonvulsants

July 15, 2006

July 15, 2006 from ObGynNews

Historically, lithium has been a mainstay of treatment for bipolar disorder. However, over the last decade, anticonvulsant drugs such as sodium valproate and lamotrigine (Lamictal) have become more widely used to treat this disorder.

The use of lithium in the first trimester is associated with a 0.05%–0.1% risk for Ebstein’s anomaly, a well-described and frequently serious cardiac malformation. But data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and other international registries indicate that first-trimester exposure to sodium valproate is associated with an 8%–10% risk of major congenital malformations, notably neural tube defects and cardiac malformations.

As a result, many clinicians have been relieved to have the option of lamotrigine, which is an effective treatment for bipolar disorder and for which there had been extremely reassuring reproductive safety data over the last 5–7 years.

And until recently, several global teratovigilance programs had not found any indication that first-trimester use of this medication was associated with an increased risk for major congenital malformations.

In what is an important development, recent data from the NAAED registry note a prevalence rate of 2.7% for overall major malformations; however, five infants (8.9/1,000) had oral clefts. (See accompanying article.)

The baseline incidence of oral clefts in the general population has been calculated to be between 0.5 and 2.16 per 1,000 births; thus the data from the NAAED registry suggest at least a fourfold increase in the risk of cleft lip and palate or an absolute risk of approximately 0.9%. Interestingly, in five other registries surveyed, the frequency of oral clefts was 2.5 per 1,000 births, far less than reported by the NAAED Registry.

So how is the clinician to understand these new data, which suggest a signal of teratogenic risk, and how do the data inform the clinical care of patients who rely on the medication for control of chronic relapsing illnesses such as epilepsy or bipolar illness?

While stopping medication for the first trimester may appear to be an option for patients with bipolar disorder, unfortunately, a significant proportion of bipolar patients who do so will relapse.

Pregnancy does not appear to protect women with bipolar disorder against relapse if the mood stabilizer they are using is discontinued: In both a retrospective and prospective study, approximately 50% of patients relapsed during the first 6 months of pregnancy following discontinuation of mood stabilizer. It is also noteworthy that women with bipolar disorder are already at a fivefold increased risk for postpartum depression, compared with the general population, a risk that increases further if they relapse during pregnancy.

Therefore, many women with bipolar disorder who want to conceive are caught between a rock and a hard place, because many compounds used to treat bipolar disorder are either known teratogens, or are agents for which the available reproductive safety data are extremely sparse, such as the atypical antipsychotics, i.e., olanzapine (Zyprexa), risperidone (Ripserdal), quetiapine (Seroquel), and aripiprazole (Abilify).

Clinicians need to work collaboratively with patients to make treatment decisions, making every effort to minimize risk of relapse and fetal risk, realizing that some patients may have to assume some risk if they are to sustain affective well-being during pregnancy. For women who are on lamotrigine and are planning to conceive, the patients and prescribing clinician should now discuss the increased risk for oral clefts.

Patients who require treatment with a mood stabilizer, particularly those with recurrent disease, may consider a trial of lithium, which, while a teratogen, is associated with an extremely small risk for a cardiovascular malformation.

Certainly, the risk associated with lamotrigine is dramatically more modest than the risk associated with first-trimester exposure to sodium valproate, and many patients may elect to continue lamotrigine.

While it may seem intuitive to consider one of the atypical antipsychotics as an alternative to lamotrigine or lithium, given their efficacy in bipolar illness, the total absence of systematically derived data regarding the reproductive safety of atypicals makes them a less attractive alternative, and frankly the last resort, as compared with medications with known reproductive safety data.

When drug choice during pregnancy is considered, proceeding with a drug with known small risks as opposed to one with totally unknown risks is advantageous, particularly if the known risk is a modest one, which is the case with lamotrigine and lithium.

Ultimately, the clinician is left having to make decisions on a case-by-case basis, in collaboration with the patient, realizing that no decision is absolutely risk-free. But decisions can be made that minimize morbidity associated with recurrence of bipolar illness, as well as prenatal exposure to any potentially harmful compound.

When presented with the options, women may make very different decisions. Some women in fact may decide to assume a small risk of oral cleft over a 0.05% risk for a heart malformation because they feel that oral clefts can be repaired more easily, while the morbidity and mortality of Ebstein’s anomaly is high, even though the risk is exceedingly small. That is why these decisions have to be made individually, because such decisions will be made not based on relative risk or even absolute risk but rather on each patient’s perception of risk.

DR. LEE COHEN directs the perinatal psychiatry program at Massachusetts General Hospital. He is a consultant to manufacturers of several antidepressant drugs, including paroxetine and other SSRIs.