Dear Readers:
We are pleased to bring you the September issue of The Women’s Mental Health Bulletin, the newsletter for the MGH Center for Women’s Mental Health. You may notice that the “look” of our newsletter has changed; with the launch of our new website in March, we also enhanced our newsletter and blog. If you have not yet had the opportunity to visit our new site, we encourage you to explore the site a bit and browse our updated content.
The current newsletter issue focuses on the use of the newer anti-psychotic medications during pregnancy. These agents are now being used widely to treat a spectrum of psychiatric disorders; however, information regarding their reproductive safety remains limited. Several case vignettes illustrate the difficulties in making decisions regarding the use of these medications in women who are either pregnant or planning to conceive.
This issue also reviews research by Dr. Hadine Joffe on Lunesta (eszopiclone) for the treatment of insomnia, depression and anxiety in peri- and postmenopausal women. Data suggest that improvement in sleep in women with hot flashes can also be associated with improvement in mood symptoms and overall quality of life. We are including an important article on the FDA’s proposal to revise prescription drug labeling, as this proposal will have a significant impact on how physicians and patients evaluate reproductive safety information for medications used during pregnancy. We invite you to share your comments on this FDA initiative on our blog.
Please note that the newsletter is only one of the ways to access the latest information in the rapidly evolving field of reproductive psychiatry. Our blog is updated weekly, and here you will find articles on topics such as:
- Citalopram for the Treatment of Menopausal Hot Flushes
- SSRI Antidepressants and Risk for Bone Loss
- Maternal Stress and Infant Sleep Problems
- Infertility Treatment and Risk for Depression
Our goal is to make our recently redesigned website an important resource for both patients and clinicians. As always, all of our newsletters are archived on our website. Later this fall, we will post a clinical case online, giving our readers an opportunity to engage, to ask questions and share their clinical opinions. We thank you for making our website a success and welcome your comments and suggestions.
Sincerely,
Ruta Nonacs, MD PhD
Editor-in-Chief, www.womensmentalhealth.com
Use of Atypical Antipsychotic Drugs During Pregnancy
While data regarding the reproductive safety of certain psychotropic medications, including selective serotonin reuptake inhibitors and anti-epileptic drugs, have increased over the last decade, information regarding the risks of fetal exposure to antipsychotic agents remains sparse. This is particularly true for the newer atypical antipsychotics, which are increasingly being used in women of reproductive age to treat a spectrum of psychiatric disorders, including schizophrenia, bipolar disorder and depression.
To date, only a handful of prospective studies on atypical agents in pregnant women have been published. The most recent study compared pregnancy outcomes in 151 subjects exposed to a variety of atypical agents (60 to olanzapine, 49 to risperidone, 36 to quetiapine, and 6 to clozapine) to outcomes in non-exposed controls. Rates of major malformations did not differ between the two groups (McKenna et al, 2005). However, it should be noted that this is a relatively small sample.
Most of the prospectively identified cases of exposure are to risperidone (over 500), olanzapine (144), and quetiapine (42), with very few to aripiprazole and clozapine, and possibly none to ziprasidone (data from manufacturers reported in McKenna et al, 2005). Other data of the reproductive safety of atypical antipsychotic agents are derived mainly from case reports or small case series. These studies taken together do not suggest an increased risk for major malformations in infants exposed to the atypical agents.
The association of the atypical agents with weight gain, diabetes, and hypertension raises other potential safety issues when these drugs are used during pregnancy. Higher pre-pregnancy body mass index (BMI) is associated with increased risk of neural tube defects (NTDs) and possibly other negative birth outcomes in the offspring. Among women taking atypical antipsychotic agents, serum folate levels are typically low; thus women taking atypical agents may have a higher risk of neural tube defects in their infants. (Presumably increasing folate intake would diminish this risk.) Whether or not women taking atypical antipsychotics may be at greater risk for gestational diabetes has not yet been studied.
Using prospective data on gestational age and birth weight, one study reported that infants exposed to atypical antipsychotics (n=25) during pregnancy were more likely than infants exposed to typical antipsychotics (n=45) and non-exposed controls (n=38) to be large for gestational age (Newham JJ et al, 2008).
Based on the limited data available, there does not appear to be any suggestion of teratogenic risk associated with the newer atypical agents. For many women with psychotic disorders or bipolar disorder, the atypical antipsychotics represent a cornerstone of their treatment regimen, and discontinuing this drug would place them at significant risk for relapse. In this situation where the atypical antipsychotic agent is important for maintaining clinical stability, we generally recommend that women maintain treatment with this drug throughout pregnancy to minimize the risk of relapse.
For a patient who presents for evaluation before pregnancy on a low dose of an atypical antipsychotic agent as an adjunct to a mood stabilizer or antidepressant, it may make sense to switch to an antipsychotic agent for which more reproductive safety data are available, such as perphenazine (Trilafon). If the atypical agent is being used to treat anxiety or sleep disturbance, other drugs may be more appropriate choices for managing these symptoms during pregnancy.
This scenario may not always be feasible, however, because many patients present when they are already pregnant. If the patient is doing well, the clinician may be understandably reluctant to make any changes in her treatment regimen. We have typically maintained patients on atypical antipsychotics if they are already pregnant because of our concerns about clinical destabilization. However, we do recommend close monitoring for weight gain, gestational diabetes, and hypertension during pregnancy, working in close collaboration with the obstetrician.
Case 1: Ms. A is a 33-year-old woman who was first diagnosed with schizoaffective disorder at the age of 23. She has had multiple psychiatric hospitalizations over the last decade and has made several serious suicide attempts. She has tried multiple anti-psychotic medications including haloperidol, risperidone, and olanzapine. The course of her illness improved significantly after switching to clozapine. She has had no hospitalizations over the last two years. She recently discovered she was pregnant and estimates she is at 8 weeks of gestation. She is currently taking clozapine 150 mg/day.
While it well known how pregnancy affects the course of schizophrenia and schizoaffective disorder, it has been demonstrated that women with psychotic disorders, especially if they are poorly treated, tend to receive less prenatal care, have poorer nutrition, and use more tobacco, alcohol, and illicit drugs during pregnancy than women without schizophrenia. Having a psychotic episode during pregnancy also increases the risk of certain adverse outcomes, including stillbirth, prematurity, and small size for gestational age.
Although there is limited information on the use of clozapine during pregnancy, most would recommend that Ms. A. continue treatment with clozapine throughout her pregnancy and into the postpartum period. Discontinuing an antipsychotic medication in this situation would carry significant risk in a woman with a severe psychiatric illness. While there may be more data on the reproductive safety of the older, typical antipsychotic agent, switching to another agent also increases the risk of relapse, especially given her poor response to antipsychotic agents other than clozapine in the past.
Case 2: Ms. B is a 30-year-old woman with a long history of major depression. She had her first episode during her teen years and since that time has been on and off a variety of antidepressants. She estimates that she has had at least 10 episodes of depression and has been on a variety of serotonin reuptake inhibitors including fluoxetine, sertraline, and citalopram. Her last episode of depression occurred approximately two years ago and was accompanied by severe generalized anxiety, panic attacks, and sleep disturbance. She was stabilized on a regimen of citalopram 60 mg and quetiapine 50 mg qhs (which was added to treat insomnia). She has been stable on this regimen for approximately two years and is now planning a pregnancy.
Given the recurrent nature of major depression and the fact that Ms. B has had multiple depressive episodes, it would generally be recommended that Ms. B maintain treatment with an antidepressant during pregnancy to minimize her risk of relapse. It is unclear, however, if she requires ongoing treatment with quetiapine, as this medication was added during the acute phase of her illness and she has made no attempt to discontinue it since that episode. As data on the reproductive safety of quetiapine is limited, she may consider tapering it. Should sleep problems recur, rather than resuming treatment with quetiapine, other agents, such as a tricyclic antidepressant or a benzodiazepine, may be considered to manage insomnia.
Case 3: Ms. C is a 30-year-old married woman currently being treated for bipolar disorder (type II). She had her first episode of depression during her freshman year of college, which lasted about a year and resolved without any intervention. She had another, more severe episode of depression at the age of 21; this time she was treated with sertraline which worked well for her. She discontinued sertraline after about a year and remained well for about three years. She had a recurrent episode of depression and was again treated with sertraline, but after a few weeks of treatment she developed symptoms of hypomania, including increased energy and productivity, distractibility, and grandiosity. Aripiprazole was added with good results, and she has remained stable for the past four years on a regimen of sertraline 100 mg and aripiprazole 7.5 mg.
There is no data on the reproductive safety of aripiprazole. Discontinuing this drug, which is here being used as a mood stabilizer, would place her at risk of recurrent hypomania or mania. One option would be switching from aripiprazole to a typical antipsychotic agent, such as perphenazine, given that there is more data to support the reproductive safety of the older, typical agents. However, it is generally felt that the typical agents are inferior mood stabilizers.
Some might consider switching to another atypical, such as olanzapine, for which there is more data available; however, it should be recognized that the data is still very limited. Another option, as Ms. C is not yet pregnant, would be to initiate a trial with a conventional mood stabilizer, such as lithium or lamotrigine. While lithium may carry some teratogenic risk and there has been concern that lamotrigine may increase the risk of cleft lip and palate, it is generally felt that it is better to use a medication whose reproductive safety has been well-characterized – even if it carries some degree of risk — than to use a medication for which the risks are unknown.
Given the widespread use of this class of medicines across a spectrum of psychiatric disorders in women of reproductive age, we clearly need more data on the reproductive safety of this class of drugs, so that we can make well-informed decisions regarding the use of the atypical antipsychotics during pregnancy.
To gather more information regarding the reproductive safety of we are in the process of establishing an atypical antipsychotic pregnancy registry at Massachusetts General Hospital that will be similar to the North American AED registry. This registry, along with other global AED registries, has produced invaluable data on the reproductive safety of antiepileptic drugs, and it is our hope that data collected from such registries and studies on atypical antipsychotics will make it possible for women and their physicians to make more informed decisions about use of this class of medicines during pregnancy.
Ruta Nonacs, MD PhD
Lee Cohen, MD
Gentile S. Clinical utilization of atypical antipsychotics in pregnancy and lactation. Ann Pharmacother. 2004 Jul-Aug;38(7-8):1265-71. Epub 2004 May 18.
McKenna K, Koren G, Tetelbaum M, Wilton L, Shakir S, Diav-Citrin O, Levinson A, Zipursky RB, Einarson A. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. J Clin Psychiatry. 2005 Apr;66(4):444-9; quiz 546.
Kulkarni J, McCauley-Elsom K, Marston N, Gilbert H, Gurvich C, de Castella A, Fitzgerald P. Preliminary findings from the National Register of Antipsychotic Medication in Pregnancy. Aust N Z J Psychiatry. 2008 Jan;42(1):38-44.
Goldstein DJ, Corbin LA, Fung MC. Olanzapine-exposed pregnancies and lactation: early experience. J Clin Psychopharmacol. 2000 Aug;20(4):399-403.
Eszopiclone for the Treatment of Insomnia, Depressive Symptoms and Anxiety in Peri- and Post-menopausal Women
Approximately 25% of peri- and post-menopausal women experience insomnia. In women with hot flashes, repeated awakenings are the most common pattern of sleep disturbance. In a recent study presented at NCDEU, CWMH researcher Dr. Hadine Joffe presented data suggesting that the non-benzodiazepine sedative-hypnotic eszopiclone (Lunesta) is not only effective for the treatment of insomnia in women with hot flashes but may also improve depression and anxiety symptoms which frequently co-occur with sleep disturbance in peri- and early postmenopausal women.
Peri- and post-menopausal women (n=59) between the ages of 40-65 years with hot flashes and insomnia were recruited for this study. Insomnia was defined as sleep disturbance (greater than 30 minutes to sleep onset and/or at least 30 minutes wake time after sleep onset) for at least 3 nights per week for at least one month. 52.5% of the participants had depressive symptoms only, 40.7% had depression and anxiety symptoms, and 6.8% had anxiety symptoms only. Women meeting criteria for an axis I psychiatric disorder were excluded.
In this double-blind, placebo-controlled cross-over trail, participants were randomized to receive either 4 weeks of eszopiclone (3 mg) or placebo. Women who received eszopiclone noted a statistically significant improvement across all sleep parameters measured (sleep efficiency, time to sleep onset, and duration of wake time) compared to those treated with placebo. Eszopiclone appeared to improve night-time, but not daytime hot flashes. Women treated with eszopiclone also had a significant beneficial effect on depression symptoms, anxiety, and overall quality-of-life.
This study indicates that eszopiclone is an effective treatment of insomnia in peri- and post-menopausal women with hot flashes. Improvement in the quality of sleep was associated with an improvement in both mood and anxiety symptoms. These results indicate that targeting sleep disturbance in peri- and post-menopausal women who present with a constellation of menopausal symptoms may have beneficial effects on multiple symptom domains, including mood, anxiety, and quality of life.
Hadine Joffe, MD, MSc
Ruta Nonacs, MD, PhD
FDA Proposes Major Revision of Prescription Drug Labeling
The U.S. Food and Drug Administration (FDA) has proposed major revisions to prescription drug labeling in order to provide more accurate and helpful information on the effects of medications used during pregnancy and breastfeeding. As it stands, the current system used by the FDA classifies the reproductive safety of medications using five risk categories (A, B, C, D and X) based on data derived from human and animal studies. While widely used to make decisions regarding the use of medications during pregnancy, many have criticized this system of classification, indicating that this type of drug labeling is often not helpful and, even worse, may be misleading.
The newly designed system would abolish the letter categories and would include more comprehensive information discussing the potential risks and benefits to the mother and the fetus, and how these risks may change during the course of pregnancy.
The FDA has proposed to organize this information into three sections:
1) The first section, called the “Fetal Risk Summary,” would describe what is known about the effects of the drug on the fetus, and if there is a risk, whether this risk is based on information from animals or humans. The proposal calls for a risk conclusion based on the available data and provides a number of examples depending on the quality and quantity of that data. For example, one risk conclusion might be: “Human data indicate that (name of drug) increases the risk of cardiac abnormalities.” This would be followed by a summary of the most important data on the drug’s effects.
2) Another section, called “Clinical Considerations,” would include information about the effects of the use of the drug if it is taken before a woman knows she is pregnant. This section also would feature discussions about the risks of the disease to the mother and the baby, dosing information, and tell how to address complications.
3) The third section, under the heading “Data,” would describe in more detail the available data regarding use of the drug in humans and from animal studies that were used to develop the Fetal Risk Summary.
The breastfeeding section of the prescription drug labeling would provide information regarding the use of the drug while breastfeeding, including information on the amount of drug found in the breast milk and the risk of adverse events in the breastfed infant.
The public is encouraged to offer their feedback on this proposal. Comments may be submitted electronically to the FDA within 90 days via the Federal Documents Management System/eRulemaking portal at www.regulations.gov. The FDA will carefully consider the comments in preparing a final rule.
Ruta Nonacs, MD PhD
Continuing Research at the Center for Women’s Mental Health
1. BIPOLAR DISORDER IN PREGNANCY
Are you an expectant mother?
Do you have questions about bipolar disorder and antidepressants or mood-stabilizers during pregnancy?
If you are pregnant and diagnosed with bipolar disorder (or manic depression), you may be eligible for this research study. Participants meet with research coordinators and psychiatrists who specialize in bipolar illness during pregnancy.
For more information about this study, please contact Rachel at (617) 726-2912 or rvanderkruik@partners.org.
2. TREATMENT OF PREMENSTRUAL WORSENING OF DEPRESSION
Seeking women between 18-45 with PMS who have been diagnosed with depression. If you are between 18 and 45 and:
- Suffer with PMS
- Currently being treated with an antidepressant
You may be eligible for a research study at Massachusetts General Hospital evaluating how a birth control pill helps with premenstrual mood symptoms. Women who participate will receive study medication and evaluations of their mood at no cost, and will be compensated up to $450.
For information, please call: (617) 724-6540 or email afarrell2@partners.org
