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Victoria Hendrick, M.D., on Drug Interactions and Drug Side Effects Specific to Women
Victoria Hendrick, M.D.
Associate Professor of Psychiatry
UCLA School of Medicine and Olive View-UCLA Medical Center
Dr. Hendrick has disclosed that she was/is a member of the speakers bureaus for GlaxoSmithKline and Pfizer Pharmaceuticals, and has given talks on the reproductive safety of Paxil (GlaxoSmithKline) and Zoloft (Pfizer). Because of these industry relationships, the editors of The Carlat Report have edited the interview in order to resolve any possible faculty conflicts of interest regarding this educational activity.TCR: Dr. Hendrick, thanks for your return visit to the pages of TCR! I’m wondering whether, as a specialist in the psychiatric treatment of women, you can tell us about particular drug interactions that you feel we should be more aware of in treating women.
Dr. Hendrick: One of the really important interactions is with estrogen-containing birth control pills. The one that many people are aware of is with carbamazepine (Tegretol), which can induce the metabolism of hormones and thereby reduce the efficacy of the birth control pill, leading to the risk of an unwanted pregnancy.
TCR: And what are some of the other meds that can cause this interaction?
Dr. Hendrick: Oxcarbazepine (Trileptal), topiramate (Topamax), and St. John’s Wort can all speed up the metabolism of the birth control pills. Unplanned pregnancy is a problem for many reasons, including the fact that we don’t know much about the safety of the newer anti-epileptic drugs in pregnancy.
TCR: For women who are doing well on one of these inducing medications, are there any options short of changing contraceptive methods? Can the dose just be increased to account for the increased metabolism? Can lab tests determine whether the birth control pills are at effective levels?
Dr. Hendrick: No, you really can’t rely on blood levels of hormones. At the very least, you can avoid low-dose estrogen formulations that contain only 20 micrograms of estrogen. Those are, of course, the highest risk formulations to be on if a woman is going to be on, say, Trileptal. So these women should take one of the higher-dose estrogen pills. But the safest strategy is to use a different form of contraception altogether.
TCR: Are there any other interactions to be aware of regarding the anticonvulsants?
Dr. Hendrick: Yes, it is important to be aware that, once women reach menopause, anticonvulsants can play the same havoc with hormone replacement therapy. If women are on hormone replacement therapy and they start carbamazepine or oxcarbazepine or topiramate, they might start noticing that they are getting a recurrence of hot flashes and night sweats because of induced metabolism, and they might need higher doses of hormone replacement.
TCR: Are there any interaction concerns regarding Lamictal (lamotrigine)?
Dr. Hendrick: Yes, and this is a different type of interaction. The estrogen in estrogen-containing oral contraceptives can increase the metabolism of the Lamictal, and Lamictal levels can be reduced very dramatically – by 40-60%. This interaction can pose particular problems while women are starting the medication, because Lamictal must be gradually titrated to minimize the risk of Stevens Johnson syndrome. If women are starting or coming off the birth control pills, it is important for clinicians to be aware that blood levels can vary quite widely. A particular danger would be that a women discontinues the Pill midway through a titration, which could result in a dramatic increase in serum Lamictal levels.
TCR: So what are your recommendations?
Dr. Hendrick: What I recommend to patients is that during the period of titration on Lamictal, they make no changes to their contraception regimen. If they are going to get on the birth control pill, they should do it before they start the Lamictal, and if they are going to come off it, they should do that before they start the Lamictal. I recommend that they don’t make the change during that six-month titration period.
TCR: Moving now to the issue of medication side effects, are there any important ones that are specific to women?
Dr. Hendrick: One of the most important ones, and it has been a controversial one, is the relationship between polycystic ovary syndrome (PCO) and valproate (Depakote). A majority of the studies have found evidence that there is a connection between use of valproate and an increased incidence of irregular menses, elevated androgen levels, and polycystic ovary syndrome. So even though the jury is still out on this, I think it is still worthwhile for clinicians who are treating young women on valproate to be vigilant for PCO-like changes.
TCR: Specifically, what should we be looking for?
Dr. Hendrick: Briefly, PCO is defined by chronic anovulation and evidence of elevated androgen. Women will develop irregular menses, hirsutism and acne. On labs, androgen levels will be elevated, including testosterone, androstenedione, and DHEA. Readers should know that there have been some inconsistencies in the literature, but over the last decade there have been more and more studies endorsing this valproate-PCO connection.
TCR: And what is the presumed pathophysiological mechanism?
Dr. Hendrick: Valproate appears to lead to both weight gain and insulin resistance, and elevated insulin levels inhibit the enzymes that transform testosterone into estrogen. The elevated testosterone then initiates the cycle of hormonal dysregulation that leads to PCO.
TCR: What are your specific clinical recommendations?
Dr. Hendrick: I recommend that clinicians ask women on valproate to keep a menstrual diary, in order to see if there is any irregularity in the menstrual pattern after beginning the medication. We should also ask about facial hair and temporal pattern balding, both of which are evidence of hirsutism. If necessary, order androgen levels, making sure to include all three androgens on the lab slip: testosterone, androstenedione, and DHEA.
TCR: We have also heard a lot of concerns about Depakote as a teratogen as well.
Dr. Hendrick: Yes, and there has been some new literature on this. It has been known for a while that there is a link between Depakote and neural tube defects. The risk was quoted at about 1-3 percent, which is a pretty substantial risk. But now the risk has been raised to closer to 5-6 percent, so it looks like it is even more teratogenic than what was previously believed. The mechanism there seems to be the anti-folate properties of Depakote, since women need folate early in pregnancy for the formation of the embryo’s neural tube. That is what makes Depakote so teratogenic, the anti-folate properties, and even giving women folate supplementation doesn’t seem to be sufficient to prevent this risk. So the best thing is to avoid Depakote in women of reproductive age who are not using contraception reliably.
TCR: Any other side effects that have come up specific to women?
Dr. Hendrick: The other side effect that you see mostly in the neurologic literature but that I think is worth pointing out for us in psychiatry is the effect that anticonvulsant drugs like carbamazepine (Tegretol) can have on vitamin D metabolism. Women, especially as they get to be menopausal, can be at greater risk for bone loss if they are on medication that speeds up the metabolism of vitamin D, and carbamazepine is one of these medications. This could be a risk for men as well, but menopausal women are more vulnerable to osteoporosis and they might not be ideal candidates to be on a medication like carbamazepine.
TCR: Do both oxcarbazepine (Trileptal) and topiramate (Topamax) also induce vitamin D metabolism? Dr. Hendrick: Yes. TCR: Since we have a bit of space left, let’s change tracks. Are there any new studies relevant to medications and pregnancy that clinicians should be aware of ?
Dr. Hendrick: There was a paper that came out a few weeks ago on antipsychotic medication which is real boon to the field because there has been very little on antipsychotic medications (J Clin Psychiatry 2005; 66:444-9). It covered Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine), so we finally have some published data on some of these newer antipsychotic agents. It showed that there were no adverse outcomes linked with any of the newer antipsychotic agents. Until that came out, most of the data we had was from the Eli Lilly registry on Zyprexa. But now we have about 50 exposures in this paper on Risperdal , which is not a ton of data, but it is enough to allow me several options in a patient who has a need for antipsychotic medication in pregnancy.
TCR: Thank you Dr. Hendrick.
General PsychiatryDr. Hendrick: One of the really important interactions is with estrogen-containing birth control pills. The one that many people are aware of is with carbamazepine (Tegretol), which can induce the metabolism of hormones and thereby reduce the efficacy of the birth control pill, leading to the risk of an unwanted pregnancy.
TCR: And what are some of the other meds that can cause this interaction?
Dr. Hendrick: Oxcarbazepine (Trileptal), topiramate (Topamax), and St. John’s Wort can all speed up the metabolism of the birth control pills. Unplanned pregnancy is a problem for many reasons, including the fact that we don’t know much about the safety of the newer anti-epileptic drugs in pregnancy.
TCR: For women who are doing well on one of these inducing medications, are there any options short of changing contraceptive methods? Can the dose just be increased to account for the increased metabolism? Can lab tests determine whether the birth control pills are at effective levels?
Dr. Hendrick: No, you really can’t rely on blood levels of hormones. At the very least, you can avoid low-dose estrogen formulations that contain only 20 micrograms of estrogen. Those are, of course, the highest risk formulations to be on if a woman is going to be on, say, Trileptal. So these women should take one of the higher-dose estrogen pills. But the safest strategy is to use a different form of contraception altogether.
TCR: Are there any other interactions to be aware of regarding the anticonvulsants?
Dr. Hendrick: Yes, it is important to be aware that, once women reach menopause, anticonvulsants can play the same havoc with hormone replacement therapy. If women are on hormone replacement therapy and they start carbamazepine or oxcarbazepine or topiramate, they might start noticing that they are getting a recurrence of hot flashes and night sweats because of induced metabolism, and they might need higher doses of hormone replacement.
“If women are on hormone replacement therapy and they start carbamazepine or oxcarbazepine or topiramate, they might start noticing that they are getting a recurrence of hot flashes and night sweats because of induced metabolism, and they might need higher doses of hormone replacement.”
– Victoria Hendrick, M.D.
TCR: Are there any interaction concerns regarding Lamictal (lamotrigine)?
Dr. Hendrick: Yes, and this is a different type of interaction. The estrogen in estrogen-containing oral contraceptives can increase the metabolism of the Lamictal, and Lamictal levels can be reduced very dramatically – by 40-60%. This interaction can pose particular problems while women are starting the medication, because Lamictal must be gradually titrated to minimize the risk of Stevens Johnson syndrome. If women are starting or coming off the birth control pills, it is important for clinicians to be aware that blood levels can vary quite widely. A particular danger would be that a women discontinues the Pill midway through a titration, which could result in a dramatic increase in serum Lamictal levels.
TCR: So what are your recommendations?
Dr. Hendrick: What I recommend to patients is that during the period of titration on Lamictal, they make no changes to their contraception regimen. If they are going to get on the birth control pill, they should do it before they start the Lamictal, and if they are going to come off it, they should do that before they start the Lamictal. I recommend that they don’t make the change during that six-month titration period.
TCR: Moving now to the issue of medication side effects, are there any important ones that are specific to women?
Dr. Hendrick: One of the most important ones, and it has been a controversial one, is the relationship between polycystic ovary syndrome (PCO) and valproate (Depakote). A majority of the studies have found evidence that there is a connection between use of valproate and an increased incidence of irregular menses, elevated androgen levels, and polycystic ovary syndrome. So even though the jury is still out on this, I think it is still worthwhile for clinicians who are treating young women on valproate to be vigilant for PCO-like changes.
TCR: Specifically, what should we be looking for?
Dr. Hendrick: Briefly, PCO is defined by chronic anovulation and evidence of elevated androgen. Women will develop irregular menses, hirsutism and acne. On labs, androgen levels will be elevated, including testosterone, androstenedione, and DHEA. Readers should know that there have been some inconsistencies in the literature, but over the last decade there have been more and more studies endorsing this valproate-PCO connection.
TCR: And what is the presumed pathophysiological mechanism?
Dr. Hendrick: Valproate appears to lead to both weight gain and insulin resistance, and elevated insulin levels inhibit the enzymes that transform testosterone into estrogen. The elevated testosterone then initiates the cycle of hormonal dysregulation that leads to PCO.
TCR: What are your specific clinical recommendations?
Dr. Hendrick: I recommend that clinicians ask women on valproate to keep a menstrual diary, in order to see if there is any irregularity in the menstrual pattern after beginning the medication. We should also ask about facial hair and temporal pattern balding, both of which are evidence of hirsutism. If necessary, order androgen levels, making sure to include all three androgens on the lab slip: testosterone, androstenedione, and DHEA.
TCR: We have also heard a lot of concerns about Depakote as a teratogen as well.
Dr. Hendrick: Yes, and there has been some new literature on this. It has been known for a while that there is a link between Depakote and neural tube defects. The risk was quoted at about 1-3 percent, which is a pretty substantial risk. But now the risk has been raised to closer to 5-6 percent, so it looks like it is even more teratogenic than what was previously believed. The mechanism there seems to be the anti-folate properties of Depakote, since women need folate early in pregnancy for the formation of the embryo’s neural tube. That is what makes Depakote so teratogenic, the anti-folate properties, and even giving women folate supplementation doesn’t seem to be sufficient to prevent this risk. So the best thing is to avoid Depakote in women of reproductive age who are not using contraception reliably.
TCR: Any other side effects that have come up specific to women?
Dr. Hendrick: The other side effect that you see mostly in the neurologic literature but that I think is worth pointing out for us in psychiatry is the effect that anticonvulsant drugs like carbamazepine (Tegretol) can have on vitamin D metabolism. Women, especially as they get to be menopausal, can be at greater risk for bone loss if they are on medication that speeds up the metabolism of vitamin D, and carbamazepine is one of these medications. This could be a risk for men as well, but menopausal women are more vulnerable to osteoporosis and they might not be ideal candidates to be on a medication like carbamazepine.
TCR: Do both oxcarbazepine (Trileptal) and topiramate (Topamax) also induce vitamin D metabolism? Dr. Hendrick: Yes. TCR: Since we have a bit of space left, let’s change tracks. Are there any new studies relevant to medications and pregnancy that clinicians should be aware of ?
Dr. Hendrick: There was a paper that came out a few weeks ago on antipsychotic medication which is real boon to the field because there has been very little on antipsychotic medications (J Clin Psychiatry 2005; 66:444-9). It covered Zyprexa (olanzapine), Risperdal (risperidone) and Seroquel (quetiapine), so we finally have some published data on some of these newer antipsychotic agents. It showed that there were no adverse outcomes linked with any of the newer antipsychotic agents. Until that came out, most of the data we had was from the Eli Lilly registry on Zyprexa. But now we have about 50 exposures in this paper on Risperdal , which is not a ton of data, but it is enough to allow me several options in a patient who has a need for antipsychotic medication in pregnancy.
TCR: Thank you Dr. Hendrick.
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