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Ask the Mental Health Expert Archives 2001-2004

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Trileptal as Mood Stabilizer?

Q. Do you know of any studies concerning the use of Trileptal as a mood stabilizer, specifically concerning the effects on pregnancy, at doses of 75-150 mg every day? I am also curious about studies concerning the use of Klonopin for insomnia at doses of .25-1 mg at bedtime and any specific effects on pregnancy at this low dosage. Can you help me?

A. Trileptal (oxcarbazepine) is under active investigation as an anti-manic agent and a mood stabilizer; however, there are very few controlled studies done in the U.S. within the past few years, and we are dependent mainly on older European studies for data on efficacy.

These data suggest that oxcarbazepine has antimanic effects comparable to those of lithium and haloperidol. (Emrich HM. Studies with oxcarbazepine (Trileptal) in acute mania. Int Clin Psychopharmacol 1990;5:83-8). However very limited controlled evidence supports the use of oxcarbazepine for bipolar depression or prophylaxis.

In terms of Trileptal's risk in pregnancy, here, too, we have limited data. The statement in the current Physicians' Desk Reference sums it up pretty well: "There are no adequate and well-controlled clinical studies of Trileptal in pregnant women; howerver, Trileptal is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Given this fact, and the results of... animal studies [showing that Trileptal may be associated with fetal abnormalities] ...it is likely that Trileptal is a human teratogen. Trileptal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus." [See Bennett et al, J Pharmacol Exp Ther 1996 Dec;279(3):1237-40 for animal data].

As you might guess, there are virtually no controlled data in humans on dose effects of this drug during pregnancy. Regarding Klonopin [clonazepam], this benzodiazepine is ordinarily not prescribed for primary insomnia, though there is no pharmacological reason it couldn't be used for this condition.

There is actually a study by Kales et al (J Clin Psychopharmacol 1991 Jun;11(3):189-93) in which clonazepam 0.5 mg was evaluated in a sleep laboratory study of 6 insomniac patients. The 16-night protocol consisted of 4 placebo-baseline nights, 7 nights of drug administration and 5 placebo-withdrawal nights. Clonazepam produced a significant decrease in total wake time initially (nights 5-7), as well as with continued administration (nights 9-11). However, rebound insomnia was seen with drug discontinuation, which is also true with other benzodiazepines.

With respect to clonazepam and pregnancy, once again, the data are limited. A recent Hungarian study by Eros et al (Eur J Obstet Gynecol Reprod Biol 2002 Mar 10;101(2):147-54) examined the association between nitrazepam, medazepam, tofisopam, alprazolam and clonazepam treatments during pregnancy and prevalence of different congenital abnormalities (CAs). Of 38,151 pregnant women who had babies without any defects (population control group), 75 (0.20%) were treated with these five benzodiazepines during pregnancy. Of 22,865 pregnant women who delivered offspring with CAs, 57 (0.25%) had benzodiazepine treatment.

The occurrence of five benzodiazepine treatments during the second and third months of gestation, i.e. in the critical period for most major CAs, did not show significant differences in matched case-control pairs. The authors concluded that treatment with the five benzodiazepines studied during pregnancy did not present detectable teratogenic risk to the fetus in humans; however, the amount of information was limited for different CAs. In contrast, a study by Samren et al (Ann Neurol 1999 Nov;46(5):739-46) found that clonazepam, in combination with other antiepileptic drugs, showed a significantly increased relative risk of producing congenital anomolies.

I don't believe we have enough data to know if there is a clear dose-related effect with clonazepam and fetal abnormalities, though one might posit that lower doses are less harmful than higher ones. Finally, keep in mind that after the first trimester of pregnancy--after the period of major organ formation--the risk of psychotropic drugs on the developing fetus are substantially less, at least in terms of teratogenicity. As always, a careful risk/benefit discussion with the patient and her obstetrician is a good practice.

September 2003

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