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From Medscape Psychiatry & Mental Health

Expert Interview

Bipolar Disorders and Women: Special Considerations. An Expert Interview With Adele Casals Viguera, MD

Posted 06/24/2005

Editor's Note:

How do the clinical characteristics of women with bipolar disorder differ from those of men? How should you prescribe medications before, during, and after pregnancy? On behalf of Medscape, Randall White, MD, interviewed Adele Casals Viguera, MD

Medscape: Compared with men, do women with bipolar disorder have particular clinical characteristics?

Adele Casals Viguera, MD: This disorder is equally distributed among men and women, unlike major depression, from which women are twice as likely to suffer than men. There are specific characteristics that women tend to have: more depressed states, more rapid cycling, and greater comorbidity, which complicate the management of the disorder. They're also more likely to suffer from mixed states.

Medscape: You did a survey of women with bipolar disorder who had received reproductive counseling and found that 45% were advised by clinicians to avoid pregnancy.[1] How should psychiatrists advise their female patients who are of reproductive age?

Dr. Viguera: I think, unfortunately, it's only in the last 10 to 15 years that we're gradually gaining enough information to provide guidance for these women: information on the reproductive safety of the various medications that we use, on the risk for relapse when medication is stopped, and on the impact of untreated illness. There is information available to clinicians to help guide these women; however, I don't think the message has gotten out there, and our group recently launched a Web site, which has a lot of information.[2] There are other groups across the country that also specialize in women's mental health: In Pittsburgh, Dr. Kathy Wisner; and at Emory University, the Women's Mental Health Program, under the directorship of Dr. Zachary Stowe.

Medscape: Are there any situations in which it would be appropriate for a clinician to advise against pregnancy?

Dr. Viguera: Yes, I think there could be circumstances when one would say this is not a good idea, but it's actually quite rare in my experience.

Medscape: Does pregnancy affect the risk for relapse of bipolar disorder?

Dr. Viguera: We're not entirely sure. We found in our study that what predicted the greatest risk was stopping medication.[3] It's almost as if stopping maintenance medication trumps everything else; it's such a powerful risk factor, it's hard to tease out whether pregnancy is a risk factor in itself. I would say it probably is, but we really haven't been able to clarify that yet.

Medscape: In your study of women with bipolar disorder who discontinued lithium in pregnancy, you found some differences in episode type among the pregnant women compared with nonpregnant women.[3] What were those?

Dr. Viguera: What we found was that in pregnancy and the postpartum period, the women relapsed into a depressive state or a mixed state 80% of the time. Twenty percent of the time they experienced mania or hypomania. We were somewhat surprised by that, although other investigators have found that most nonpregnant patients who have bipolar disorder spend most of their time in a depressed state.

Medscape: Medications for treating bipolar disorder vary in teratogenic potential. Can you briefly outline the most important risks of mood stabilizers to the developing human?

Dr. Viguera: Lithium is one of the best-known teratogens and the oldest mood stabilizer. Initially, the teratogenic risk for lithium was thought to be quite high. In the 1970s, there was the lithium baby registry, and from those data the risk for Ebstein's anomaly was noted.[4] Ebstein's anomaly is right ventricular hypoplasia and displacement of the tricuspid valve; it can vary in severity, and in its most severe form is associated with 100% mortality.

The baseline risk for that anomaly in the general population is very rare -- it occurs in 1 in 20 000. But in this particular group of children, it occurred in 1 in 50. So that really scared people away from using lithium during pregnancy, and if a woman did get pregnant on lithium, she was counseled to have a termination. If she was on lithium and wanted to become pregnant, she was generally told that remaining on lithium was contraindicated. But between the 1970s and 1990s, better studies -- case-control and cohort studies -- were done, which showed that the risk was much smaller than we had thought for this heart defect. Instead of 1 in 50, it appeared in 1 in 1000 to 2000, and that really altered the overall risk-benefit assessment.

Despite the fact that it's still an elevated risk compared with baseline, the absolute risk of 1 in 1000 to 2000 is quite low, and for these women who are at high risk for relapse, I've found that they're willing to tolerate that. So lithium is now frequently used in pregnancy. If we can avoid using it in the first trimester, we do try to, but for patients with very brittle disorder, we let them take it through the first trimester.

After the first trimester, we're very aggressive about reintroducing the drug to patients who stopped taking it during that time in order to maintain euthymia throughout pregnancy. We found that becoming ill during pregnancy is one of the strongest predictors for postpartum relapse. Patients who remained well in pregnancy had a better postpartum prognosis than patients who became ill in pregnancy and had medicine reintroduced.[3]

The other major mood stabilizer category is anticonvulsants, and we are fortunate that in the last 10 years or so, we have gathered more information from neurologists on the teratogenic potential of divalproex ( Depakote ) and carbamazepine ( Tegretol ). Those drugs are considered first-generation anticonvulsants. In general, unlike lithium, the anticonvulsants tend to have more global effects, so they are associated with craniofacial abnormalities; limb malformations; and most notably, spina bifida. Recently, we have received new information on the risk associated with divalproex from the Antiepileptic Drug Pregnancy Registry, here at Massachusetts General Hospital,[5] which suggests that the risk for overall malformations with divalproex is higher than we had thought: It's close to 10%.[6]

Lamotrigine ( Lamictal ) is considered a newer-generation anticonvulsant, and the pharmaceutical company established an international lamotrigine pregnancy registry. It just released the findings, which involved over 400 first-trimester exposures to lamotrigine monotherapy.[7] The overall risk for major malformations is about 2.9%, which falls between 2% and 4%, the baseline risk for major malformations in the general population. I always educate my patients that we're all at risk for having a child with a birth defect. When you evaluate these medications, you have to ask the question, "Do they increase that baseline risk?"

So far, of the anticonvulsants, lamotrigine seems relatively safe with respect to risk for major malformations, compared with divalproex.

Medscape: Can you say anything about antipsychotics and the risk for fetal anomalies?

Dr. Viguera: The reproductive safety data on typical antipsychotics suggest that they do not increase the risk for major malformations, so we tend to use them often in pregnancy. However, the atypical neuroleptics, although they are effective in treating bipolar disorder, lack sufficient reproductive safety data at this time. It's not that we avoid them, because some patients are only stable because of those medicines, but given a choice, we would lean more toward the older neuroleptics.

Medscape: You wrote in a review article in the Canadian Journal of Psychiatry that choosing treatment for a woman who wishes to become pregnant "depends on the severity of the individual patient's illness."[8] How should the clinician use that guideline to formulate a treatment plan?

Dr. Viguera: Severity of illness is a judgment call that the clinician and the patient make. What you are looking for are patients who've had multiple episodes -- more than 3 or 4; patients who do not get well between episodes; patients who, when they become ill, become very ill and immediately go into a psychotic mania or get severely depressed; and patients who report that they became ill very quickly when they stopped their medication. The actual predictors haven't been clearly worked out yet, but severity of illness refers to the number of episodes and whether the patient required hospitalization or was suicidal. In those cases, you'd want to maintain them on medicine.

Medscape: So for those patients, the choice would be lithium or lamotrigine or an antipsychotic?

Dr. Viguera: I think it's a tricky question. A lot of people ask, "Which would you use, lithium or lamotrigine?" My response is that it depends on the characteristics of the patient's illness. I don't think that lithium and lamotrigine are necessarily interchangeable. There are some patients who respond beautifully to lithium, while there are others who do not respond at all to lithium and do better on anticonvulsants. I think it's very important to get a good history to find out if they've ever been on lithium. If they haven't, I think it's worth a try, certainly in the prepregnancy planning phase.

Now, a lot of residents and people in training are not getting experience using lithium; it's sort of the forgotten mood stabilizer. But it can be incredibly effective, particularly for patients who have recurrent manias. So it really depends on the subtype or flavor of the bipolar disorder.

Medscape: What is the risk for a postpartum episode in a woman with bipolar disorder? How should that be managed?

Dr. Viguera: I conceptualize pregnancy and postpartum as separate risk periods. We discussed how it's not clear whether pregnancy is destabilizing or not, but it's very well-established that postpartum is a time of high risk, and the greatest risk occurs within the first 6 weeks. For these women, the analogy I like to draw is it's like walking along a cliff -- they are at very high risk for falling into depression, mania, or a psychosis, which is basically a manic episode. Postpartum psychosis is rare in the general population -- it occurs in 1 in 1000. But in women with bipolar disorder, the risk is about 20% to 30%. What's unique about postpartum psychosis is that it occurs early on, within 24 to 48 hours after delivery, and it's a psychiatric emergency because of the 4% risk of infanticide. These women need to be hospitalized and treated with either electroconvulsive therapy or with a mood stabilizer and an antipsychotic.

Overall, in the literature, the risk for relapse for women with bipolar disorder is 50%, but based on the latest data from ours and other groups, it's probably closer to 60% to 70%. This is for women who are not on any medicine as they approach the postpartum. The current standard of care, given the high risk for relapse, is to put patients back on their mood stabilizer prior to delivery. What has not been worked out is the best timing for that. Is it weeks before delivery or immediately after delivery? This is what we call postpartum prophylaxis.

There have been only 5 studies looking at lithium for postpartum prophylaxis, and they all showed that if women restarted their lithium proximate to delivery, they could reduce their risk for relapse from 50% to, on average, 10%, so it significantly reduces risk.[4,8]

More recently, Katherine Wisner published a study in which women were given divalproex immediately postpartum.[9] There were 26 patients, randomized either to divalproex or to close monitoring. She [and her team] found no differences between the 2 groups. What I think happened in that study is that introducing the medication right after delivery is too late. It's probably better to get the woman on a therapeutic dose well before delivery. We tend to put patients back on their medicine around 36 weeks of gestation, or sometimes we reintroduce it right after the first trimester, because we know that becoming ill during pregnancy is the strongest predictor for becoming ill postpartum.

References

Bouffard S, Viguera AC, Cohen LS. Bipolar women and pregnancy: weighing the risks following antenatal consultation. New investigator poster session. American Psychiatric Association; 2001; New Orleans, Louisiana.

Massachusetts General Hospital Center for Women's Mental Health. Available at: http://www.womensmentalhealth.org/ . Accessed June 15, 2005.

Viguera AC, Nonacs R, Cohen LC, Tondo L, Murray A, Baldessarini RJ. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry. 2000;157:179-184. Abstract

Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry. 2004;161:608-620. Abstract

Massachusetts General Hospital Antiepileptic Drug Pregnancy Registry. Available at: http://aedpregnancyregistry.org/ . Accessed June 15, 2005.

Wyszynksi DF, Nambisan M, Surve T, Alsdorf RM, Smith CR, Holmes LB. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology. 2005;64:961-965. Abstract

Cunnington M, Tennis P, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology. 2005;64:955-960. Abstract

Viguera AC, Cohen LS, Baldessarini RJ, Nonacs R. Managing bipolar disorder during pregnancy: weighing the risks and benefits. Can J Psychiatry. 2002;47:426-436. Abstract

Wisner KL, Hanusa BH, Peindl KS, Perel JM. Prevention of postpartum episodes in women with bipolar disorder. Biol Psychiatry. 2004;56:592-596. Abstract

Funding Information

Supported by an independent educational grant from GlaxoSmithKline.

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Thank you!  I am off to see my shrink tomorrow and all of this type of info has been invaluable to help me work out what is the best answer for my situation.  Information like this helps me to feel I have a say in how my own treatment regime can be accommodated without being bullied into what the pdoc has already decided in their head.  I am definately open to my pdoc's information but I feel confident now that I also have plenty of info to back up my own thoughts, concerns and general health concerns.

Bleu thanks you!  ;)

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Thanks so much for this. I'm currently taking lamotrigine, fluoxetine and olanzapine and it has given me balance and I've never been so well. However, I have a wonderful boyfriend and would like to get pregnant sometime in the next 6 months or so. I've seen a lot of very scary information on the net about Bipolar meds, but I'll be very honest and say I'm much more likely to believe what I read here on Crazyboards than anywhere else. I'm very aware that I would need to stop taking the olanzapine, but I don't think that will make a considerable difference to my moods, although it is balancing out the slightly higher dose of fluoxetine that I'm taking now as it's the winter months and I need further support during this time. Once I reduce the fluoxetine dose back to it's normal levels, I feel certain that I would be fine to discontinue use of the olanzapine as I've not needed it before during the lighter times of the year.

As I'm over 40, I'm doubly nervous about getting pregnant, but I may never get another opportunity, and I love this man with all my heart, and I know he loves me, so there's never really been a better time. We've only been together for 6 months so far, so I want to give it some more time until I'm utterly sure of him and to attempt to get him used to the idea. I think he's scared of babies - he's big and strong and I think he's afraid he'll break them! But I'm 43 and he's 29, and I can't wait much longer or the risk increases hugely (it's already very high)...

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