Adele Viguera, M.D.
Assistant Professor of Psychiatry, Harvard Medical School
Associate Director, Perinatal and Reproductive Psychiatry Program,
Massachusetts General Hospital
Dr. Viguera has disclosed that she is a member of the speakers bureau of GlaxoSmithKline.
TCR: Dr. Viguera, what are your responsibilities in the Perinatal and Reproductive Psychiatry Program? Dr. Viguera: Basically I am a clinical researcher. So in addition to seeing patients and doing consultations, I've been directing a research study for the last five years in which we are looking at the course of bipolar disorder during pregnancy and the postpartum period. We now have about 115 women in our cohort, and it is a naturalistic, longitudinal study, focusing on predictors and risk of relapse. And what we found so far is that a lot of patients will stop their medicines when they find out they are pregnant, but unfortunately, this puts them at high risk for getting ill. About 60-70% of pregnant bipolar patients will experience a mood episode off medication, and most of these episodes are depressive rather than manic episodes.
TCR: Wow. That's a very high relapse rate. And it's a common scenario in a psychiatric practice to have a woman with bipolar disorder come in and announce that she is pregnant and to ask us for advice about meds. How do you approach this situation? Dr. Viguera: I think a useful paradigm to keep in mind is how a neurologist approaches a pregnant woman with epilepsy. In that situation it is very clear that she needs to be on a maintenance medication so that she will be seizure-free, because we know seizures are very detrimental to the well-being of the fetus. Now, the problem is, can we make the argument that untreated depression or mania is as bad as a seizure? I think we can--at least, that is certainly my bias.
TCR: Before getting into treatment issues, what are some of the prevalence figures for post-partum depression? Dr. Viguera: For women who have a prior history of unipolar depression, there is about a 30% risk of postpartum depression; this increases to 50% if she had postpartum depression in the past. For the bipolars, what has been quoted in the literature is that the risk is about 50%, but based on our current study, I think that the risk is probably closer to 70%.
Lamictal, of the anticonvulsants, is probably our first line for pregnant women with bipolar disorder who have responded to anticonvulsants in the past. - Adele Viguera, M.D.
TCR: And so do you recommend that women who have had a history of depression stay on some form of antidepressant during the pregnancy? Dr. Viguera: It depends how severe their history has been. If it has been quite severe and they have been on maintenance medication for some time, they will likely need to remain on medication during pregnancy.
TCR: What are your thoughts about the safety of SSRIs in pregnancy? Dr. Viguera: In general, I feel comfortable using most of the SSRIs, because by now we have had enough of a track record with them. Often I am guided by whatever medication the patient has responded to in the past. So, for example, if she has done well on Zoloft, I will maintain her on that. But what is complicating the picture now is that the FDA has issued a warning about using antidepressants in the third trimester because at the time of delivery, neonates may be at risk for withdrawal or discontinuation symptoms from SSRIs. [See accompanying article in this issue for more information.] Unfortunately, this warning is not based on a whole lot of literature, but it is out there in the press, and I think women will see it and panic. Our experience so far in our clinic has been that the incidence of these symptoms is exceedingly rare, and if it does happen, it is a transient phenomenon and will generally resolve within 24-48 hours. So the FDA warning hasn't necessarily changed our practice.
TCR: Within the family of SSRIs, are there any that have a better or worse track record in pregnancy? Dr. Viguera: The most safety information has been collected on Prozac, followed by Zoloft. We don't have as much information on Effexor (venlafaxine), which is an SNRI. There is a very limited database on that--about 150 cases. Nor do we have a lot of information on Luvox (fluvoxamine) or Lexapro (escitalopram). Wellbutrin is a confusing case because it has been given a relatively safe "Category B" labeling in the PDR versus most of the other psychotropics which are "Category C." Actually, we don't have as much information about it as we do about the SSRIs, so we try not to use it. But if a patient has responded to Wellbutrin and has failed SSRIs, we will continue Wellbutrin.
TCR: What about mood stabilizers? When will you recommend that a woman be on a mood stabilizer during her pregnancy, if ever? Dr. Viguera: Well, again, it is all driven by the history. In very brittle bipolar disorder, women might be willing to accept the risk of taking a mood stabilizer. For instance, with lithium, the risk of a cardiac defect with first trimester exposure is between 1 in 1,000 and 1 in 2,000 deliveries. Some women will say, "Well, I have been so stable for the last couple of years on lithium and I can't afford to get sick during pregnancy so I will accept that risk." And in that case we will recommend a Level II ultrasound at around 18 weeks to look at the heart morphology and make sure everything is intact.
TCR: What about anticonvulsants in pregnancy? Dr. Viguera: We try to avoid Depakote (valproic acid), especially in the first trimester, because of the increased risk of major malformations, not only spina bifida, but also cardiac anomalies. For Depakote monotherapy, the risk of anomalies is about 9%, well above the risk with lithium.
TCR: So, you'll typically have women discontinue lithium or Depakote once they find out they are pregnant, and then resume one of these when the second trimester begins? Dr. Viguera: Right. But to complicate matters a bit more, with Depakote, there is some concern about neurodevelopmental risks even with exposure in the second and third trimester. But often if patients are not lithium responders, and they have done well on Depakote, then that is a risk they may be willing to take.
TCR: Do you recommend adding folic acid to Depakote for pregnant women? Dr. Viguera: Yes we do, because Depakote can deplete folate stores. We often recommend 4 mg of folate a day throughout the first trimester.
TCR: But it sounds like it would be pretty unusual to give your blessings to a woman staying on Depakote during pregnancy. Dr. Viguera: That's true, but what happens sometimes is that they come in and they are already 8 or 9 weeks pregnant and on Depakote and we wouldn't necessarily stop it then. But if we were doing pre-pregnancy planning, we would try to get them off of it.
TCR: Are there any mood stabilizers that are safer than Depakote or lithium? Dr. Viguera: Lamictal (lamotrigine), of the anticonvulsants, is probably our first line if a patient is an anticonvulsant responder. We have data now from the GSK (GlaxoSmithKline) Pregnancy Registry, which shows that it looks pretty good in terms of reproductive safety. So far, the risk of major malformations with Lamictal monotherapy is around 3%, which falls within the range of the baseline risk in the general population. So, thus far, it is definitely a very good alternative to Depakote.
TCR: And if you were to have a choice between lithium and Lamictal? Dr. Viguera: We would probably still favor lithium because we have more experience with it. But it all depends on their bipolar disorder, what they respond to. Not all folks respond to lithium, so you need other alternatives.
TCR: And what about the atypical antipsychotics? Dr. Viguera: A general rule of thumb with the atypicals is that, while we would very much like to be able to use them, we just don't have enough reproductive safety data on them. We tend to rely on the typical neuroleptics, such as Trilafon (prephenazine) or Haldol (haloperidol). We favor these higher potency neuroleptics because of the lower likelihood of causing hypotension.
TCR: What about other medications that are used for agitation and insomnia, such as the benzodiazepines? Dr. Viguera: We actually do use benzodiazepines in pregnancy, and I think that alarms a lot of people. The literature on the benzodiazepines is quite confusing and controversial. But there were some meta-analyses published showing that, in cohort studies, the incidence of cleft palate (which is what benzodiazepines are associated with) is actually quite low, less than 1%. And so we use low-dose Ativan (lorazepam) and Klonopin (clonazepam) to help with insomnia throughout pregnancy.
TCR: And what about trazodone for sleep? Do you use that? Dr. Viguera: No, we don't have enough data for it. Nor do we have enough data on Benadryl (diphenhydramine), Sonata (zaleplon), or Ambien (zolpidem). However, we have a reassuring data on the safety of low-dose tricyclics, including amitriptyline, nortriptyline and desipramine, all of which can be helpful for insomnia.