Dear Readers,
We are pleased to bring you the May 2009 issue of the Women’s Mental Health Bulletin, the newsletter for the Massachusetts General Hospital Center for Women’s Mental Health. The current issue of the Bulletin includes a spotlight on the National Pregnancy Registry for Atypical Antipsychotics, our national research study established to systematically evaluate the reproductive safety of these medications.
Another article reviews research on omega-3 fatty acids for the treatment of depression in women. Soon we will have preliminary data on the use of omega-3 fatty acids for the treatment of major depression in menopausal women, and we have just launched a new study to evaluate the utility of omega-3 fatty acids for the treatment of high triglycerides and cholesterol in women and men taking atypical antipsychotic agents.
This issue also reviews a recent study from the Center which evaluated the relationship between anxiety and vasomotor symptoms in perimenopausal women. This research was presented at the most recent meeting of the North American Menopause Society.
In addition to the Women’s Mental Health Bulletin, we are beginning to send out announcements to our newsletter subscribers about new research studies at the Center for Women’s Mental Health. We see this as a way to reach out to those interested in our work; please feel free to send any feedback to admin@womensmentalhealth.org. As always, all of our current active studies are listed at the end of the newsletter and on our website.
We launched our updated website one year ago, and now have over ten thousand visitors to our site each week. This is an important online resource for health care providers and patients across the globe. As a supplement to the newsletter, we continue to publish at least one new blog post each week on our website. Recent blog posts have covered the following topics: use of Viagra to treat antidepressant-associated sexual dysfunction in women, SSRIs and neonatal distress syndrome, and a mouse model of postpartum depression. We appreciate your comments, and please let us know if there are topics you would like to see addressed in future blog posts.
As always, thank you for your interest in our Program.
Ruta Nonacs, MD PhD
Editor-in-Chief
National Pregnancy Registry for Atypical Antipsychotics
The team at the MGH Center for Women’s Mental Health is pleased to announce the establishment of the National Pregnancy Registry for Atypical Antipsychotics. This new research study will address the dearth of available prospective data on the safety of the use of atypical antipsychotics during pregnancy and their potential effects on the developing fetus and mother. The atypical antipsychotics most frequently prescribed in the United States include Abilify (aripiprazole), Clozaril (clozapine), Geodon (ziprasidone), Invega (paliperidone), Risperdal (risperidone), Seroquel (quetiapine), and Zyprexa (olanzapine). These medications are being increasingly used as primary or adjunctive therapy across a wide range of psychiatric disorders including bipolar disorder, schizophrenia, unipolar depression, anxiety disorders and other psychotic illnesses. These disorders are highly prevalent in women during the reproductive years. Therefore, information regarding the reproductive safety for these medications is urgently needed.
Currently, there is no consensus for systematic methods to collect such information, and the effect has been a literature that is often confusing and inconsistent in findings. To date, most of the data collected on the safety of psychotropic medications during pregnancy is from small, observational case studies or industry reports, which do not provide definitive information about reproductive safety. The majority of medication trials exclude pregnant women from enrollment or if a woman becomes pregnant during a trial, she is withdrawn from the study. Furthermore, there is no formal mandate from the U.S. Food and Drug Administration (FDA) that such information be systematically collected. Therefore, important drug safety information is often not available to women who must often face the clinical dilemma of whether to continue or discontinue their medication during pregnancy. The National Pregnancy Registry for Atypical Antipsychotics is the first hospital-based pregnancy registry for atypical antipsychotics in America to systematically and prospectively evaluate pregnancy outcomes. It is modeled after the North American Antiepileptic Drug Pregnancy Registry, which is in its eleventh year at the Massachusetts General Hospital.
Pregnant women who are currently taking one or more atypical antipsychotics are eligible and encouraged to enroll in the Registry by calling our toll free number (1-866-961-2388). Information regarding maternal and neonatal outcomes is obtained by study staff over three prospective phone interviews:
Interview 1: The first interview is conducted early in pregnancy (ideally during the first 16 weeks of pregnancy), and takes approximately 20 minutes. This interview records baseline information about the status of a woman’s pregnancy, including her medical history, psychiatric information, current and past pregnancy information, habits, and demographic information.
Interview 2: The second interview is conducted during the seventh month of pregnancy, and takes approximately 10 minutes. Any change in medication is recorded, as are changes in the woman’s physical and psychiatric health and her pregnancy.
Interview 3: The third interview is conducted after the woman delivers her baby, and takes approximately 10 minutes. Again, any changes in medication or health are recorded. Detailed information about the pregnancy and delivery is recorded to evaluate both maternal and neonatal health outcomes. Following the final interview, and with the woman’s consent, a copy of her medical records is obtained for review by a staff teratologist, a specialist in the effects of exposures and infant outcomes.
The primary aim of the Registry is to estimate the frequency of major malformations in infants exposed to atypical antipsychotics, but we are also interested in examining maternal and neonatal outcomes associated with the use of these medications during pregnancy. Major malformation rates among Registry participants will be compared to rates among women who are not exposed to atypical antipsychotics during pregnancy.
We at the Massachusetts General Hospital Center for Women’s Mental Health are very pleased to launch the National Pregnancy Registry for Atypical Antipsychotics. Over the past decade, pregnancy registries have emerged as an effective and efficient method for collecting important reproductive safety data. It is our hope that the inauguration of this important research initiative represents a first step in gathering critical safety information on the use of atypical antipsychotics during pregnancy. In the near future, pregnant women treated with this class of medications will be the beneficiaries of such information and therefore be better informed when making clinical decisions about treatment during pregnancy.
Adele C. Viguera, MD
Katherine Donovan, BA
Read more:
The National Pregnancy Registry for Atypical Antipsychotics: www.womensmentalhealth.org/pregnancyregistry
Cohen LS. Atypical antipsychotics in pregnancy. ObGyn News, April 2008.
Nonacs R, Cohen LS. Use of atypical antipsychotic drugs during pregnancy. Women’s Mental Health Bulletin, September 2008.
Omega-3 Fatty Acids for Depression in Women
An ideal treatment for major depressive disorder (MDD) in women would be efficacious, safe, and offer broad health benefits. MDD is prevalent in women of childbearing years, and recent research underscores the risk of recurrence of mood episodes during pregnancy. Concerns many women and their health care providers have about antidepressant exposure during pregnancy and breastfeeding increase the public health significance regarding safe non-medication treatment options.
Omega-3 fatty acids have been a topic of interest in mood disorders, with promising evidence from epidemiological, preclinical, and clinical studies that support a role in mood disorders (Freeman et al., 2006). Omega-3 fatty acids have established health benefits, with specific benefits for fetal and infant development (Kris-Etherton et al., 2003; McGregor et al., 2001). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two key omega-3 fatty acids and are the main omega-3 fatty acids studied in mood disorders. Meta-analyses of randomized controlled trials have consistently demonstrated a significant benefit of omega-3 fatty acids in major depressive disorder and bipolar depression with heterogeneity in study designs and results, and to date they have been most thoroughly studied as an augmentation strategy (Freeman et al., 2006).
Maternal omega-3 fatty acid intake has established benefits for obstetrical and infant outcomes (McGregor et al., 2001; Dunstan et al., 2006; Hibbeln et al., 2007). In animals, maternal brain DHA levels are depleted when omega-3 fatty acid intake is deficient during pregnancy (Levant et al., 2006). In the U.S., pregnant and postpartum women consume less omega-3 fatty acids than is recommended, with demand noted to be higher during pregnancy and lactation. Dietary intake during pregnancy was demonstrated to decrease further subsequent to U.S. Food and Drug Administration mercury advisories regarding fish intake during pregnancy (Benisek et al., 2000; Oken et al, 2003). Fortunately, omega-3 fatty acid capsules appear free of significant levels of mercury or other contaminants (Foran et al., 2003).
Three randomized placebo-controlled trials have been conducted for perinatal MDD. In two of three, investigators did not detect a significant difference between omega-3 fatty acids and placebo (Rees et al., 2008; Freeman et al., 2008). Su et al., (2008) found a significant benefit of omega-3 fatty acids compared with placebo in prenatal MDD. All three studies were small, and Su et al. utilized the highest dose. All were also relatively short trials, lasting up to 8 weeks. In the two studies that did not demonstrate differences between omega-3 fatty acids and placebo, both omega-3 fatty acid and placebo groups improved significantly from baseline, suggesting that other factors were associated with improvement and may have obscured the ability to detect an effect of omega-3 fatty acids, especially if they are mild to moderately effective (Rees et al., 2008; Freeman et al., 2008). Dose may be especially important to consider, as the Su et al. study used the highest dose. Omega-3 fatty acid capsules appear well tolerated by pregnant and postpartum women (Freeman et al., 2008).
As recommended by the American Heart Association, adults should eat fish at least twice per week, and those with coronary artery disease should consume at least one gram per day of EPA and DHA daily. Considering the comorbidity between medical and psychiatric conditions, and a possible adjunctive benefit of omega-3 fatty acids for individuals with mood disorders, clinicians and patients should consider the addition of omega-3 fatty acids to the treatment plans of women with mood disorders.
Marlene P. Freeman, MD
Dunstan JA, Simmer K., Dixon G, Prescott SL. Cognitive assessment at 21/2 years following fish oil supplementation in pregnancy: a randomized controlled trial. Arch Dis Child Fetal Neonatal Ed. Pediatr Res. 2006; 62(6):689-94.
Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M, Keck Jr PE, Marangell LB, Richardson AJ, Lake J, Stoll AL. Omega-3 Fatty Acids: Evidence Basis for Treatment and Future Research in Psychiatry [American Psychiatric Association Subcommittee Report]. J Clin Psychiatry. 2006. 67:1954-1967.
Freeman MP, Davis M, Sinha P, Wisner KL, Hibbeln JR, Gelenberg AJ. Omega-3 fatty acids and supportive psychotherapy for perinatal depression: a randomized placebo-controlled study. J Affect Disord. 2008;110(1-2):142-8.
Kris-Etherton PM, Harris WS, Appel, LJ, AHA Nutrition Committee, American Heart Association. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc BioI. 2003. 23(2): 151-2.
Levant B, Radel JD, Carlson SE. Reduced Brain DHA Content After a Single Reproductive Cycle in Female Rats Fed a Diet Deficient in N-3 Polyunsaturated Fatty Acids. Biol Psychiatry; 2006. 60(9):987-90.
McGregor JA, Allen KG, Harris MA, Reece M, Wheeler M, French JI. Morrison J., The omega-3 story: nutritional prevention of preterm birth and other adverse pregnancy outcomes. Obstet Gynecol Surv. 2001. 56(5 SuppI1):S1-13.
Rees AM, Austin MP, Parker GB. Omega-3 fatty acids as a treatment for perinatal depression: randomized double-blind placebo-controlled trial. Aust N Z J Psychiatry. 2008. 42(3): 199-205.
Su KP, Huang SY, Chiu TH, Huang KC, Huang CL, Chang HC, Pariante CM. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized double-blind, placebo-controlled trial. J Clin Psychiatry, 2008; 69(4):644-51.
New Research at the Center for Women’s Mental Health: Anxiety Predicts Reduction in Menopausal Hot Flashes
Recent epidemiologic studies suggest that anxiety is highly associated with menopausal hot flashes, even after adjusting for known risk factors for hot flashes, including BMI, race, smoking, and estradiol levels. Current research suggests that an interaction between serotonergic neurotransmission and estrogen may help clarify the underlying etiology of hot flashes, exemplified by a growing number of positive studies which demonstrate successful treatment of hot flashes with SSRIs. Anxiety disorders are extremely common in women (22.6% of women in the general population vs. 11.8% for men) and have been associated with serotonin dysregulation and are often treated with SSRIs. If anxiety is, in fact, associated with hot flashes, it would be an important consideration for clinicians in helping women decide which treatment options might be most effective.
At the 2008 North American Menopause Society (NAMS) meeting, researchers from the MGH Center for Women’s Mental Health presented data from a secondary analysis of clinical trials conducted at MGH that support this association. Four clinical trials assessed anxiety and hot flashes at the beginning and end of each study using standardized questionnaires:
Study 1: A six week, double-blind, placebo-controlled trial of paroxetine CR (Paxil CR) for treatment of hot flashes in menopausal women (N=56). The primary outcome measure was reduction in hot flashes, and the study found that paroxetine CR reduced hot flashes more effectively than placebo.
Study 2: A five week, cross-over, double-blind placebo-controlled study of eszopiclone (Lunesta) for the treatment of insomnia and depression in menopausal women (N=67). The primary outcome measure was improvement in sleep parameters, and the study found that compared with placebo, treatment with eszopiclone resulted in significant improvement in all sleep parameters.
Study 3: An eight week, double-blind placebo-controlled study of 17-beta-estradiol (Climera) compared to zolpidem (Ambien) for the treatment of depression and hot flashes in symptomatic menopausal women (N=86). The primary outcome of the study was change in mood symptoms. Data are currently being analyzed, but preliminary analysis suggests that both zolpidem and estradiol are more effective than placebo for the treatment of mood symptoms in women experiencing hot flashes and sleep disruption.
Study 4: A six week, open-label trial of duloxetine (Cymbalta) for the treatment of major depression in menopausal women (N=30). The primary outcome was change in mood over the course of the study, and the study found that open-label duloxetine did significantly improve mood symptoms.
The analysis of these four studies showed that improvement in anxiety symptoms consistently predicted a reduction in hot flashes, regardless of the type of treatment intervention or the condition being treated. Also, the higher a woman’s anxiety at the beginning of the study, the greater reduction in hot flashes she would experience over the course of treatment. Therefore, treatments targeting anxiety may be effective in treating hot flashes in symptomatic menopausal women.
Katherine Donovan, BA
Erica Pasciullo, BA
Cohen LS, Soares CN, Pasciullo E, Joffe H. Anxiety predicts reduction in menopausal vasomotor symptoms with hormonal and non-hormonal treatments. Poster presented at NAMS September 2008.
Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S, Ferdousi T. The role of anxiety and hormonal changes in menopausal hot flashes. Menopause 12 (3): 258-266
From Our Blog: Fetal Exposure to Valproate Associated with Lower IQ
There have long been concerns regarding the use of the anticonvulsant valproate (Depakote) during pregnancy. First trimester use of valproate has been associated with a 3-5% risk of neural tube defects, as well as an increased risk of other malformations affecting the heart, limbs, and genitals. A recent report published in the New England Journal of Medicine indicates that in utero exposure to valproate may also result in lower IQ.
In this study, researchers from the United States and the United Kingdom presented data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, a prospective, observational, multicenter study which followed women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate).
A total of 309 children were evaluated at 3 years of age. The authors reported that children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjusting for a variety of variables, including maternal IQ, maternal age, drug dosage, gestational age at birth, and maternal preconception use of folate, it was observed that on average children exposed to valproate had IQ scores 6 to 9 points lower than the scores of those exposed to the other anti-epileptic agents. It was also shown that the association between valproate and lower IQ was dose-dependent, with the worse cognitive outcomes observed in children exposed to doses of valproate higher than 1000mg/day.
These results are consistent with those of previous retrospective studies which have demonstrated poorer cognitive functioning and lower verbal IQ scores in children exposed to valproate in utero as compared to children who were either unexposed or exposed to other antiepileptic-drug monotherapies. The authors conclude that given these risks, other anticonvulsant agents are preferable in women who are planning a pregnancy.
Ruta Nonacs, MD PhD
Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; NEAD Study Group. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009 Apr 16;360(16):1597-605.
Ongoing Research at the Center for Women’s Mental Health
OMEGA-3 FATTY ACIDS FOR THE TREATMENT OF HIGH TRIGLYCERIDES AND CHOLESTEROL IN MEN AND WOMEN USING ATYPICAL ANTIPSYCHOTICS (New!)
Do you have HIGH TRIGLYCERIDE or CHOLESTEROL levels?
Are you taking an atypical antipsychotic?
If you are a woman or man ages 18-75 and:
• Have high triglycerides or high cholesterol
• Are taking one of the following medications: clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), aripiprazole (Abilify), ziprasidone (Geodon), quetiapine (Seroquel), paliperidone (Invega)?
• Are not currently taking triglyceride or cholesterol-lowering medication
You may be eligible for a research study for the treatment of your high triglycerides or cholesterol with omega-3 fatty acids.
Participants will receive study medication and monitoring of their triglyceride levels at no cost, and will be compensated up to $200 over the course of the 16 week study.
For information, please call: (617) 724-6540 or email afarrell2@partners.org
ESCITALOPRAM FOR THE TREATMENT OF POSTPARTUM DEPRESSION (New!)
Seeking women between ages 18-45 with postpartum depression.
If you are between ages 18 and 45 and:
- Gave birth within the past six months
- Began to feel depressed and anxious within 3 months of giving birth
- Are not currently taking an antidepressant
- Are not breastfeeding
You may be eligible for a research study at Massachusetts General Hospital evaluating how an FDA approved antidepressant helps treat depression after childbirth.
Women who participate will receive study medication and evaluations of their mood at no cost, and will be compensated up to $150 over the course of the 8 week study.
For information, please call: (617) 724-6989 or email kdonovan8@partners.org
NATIONAL PREGNANCY REGISTRY FOR ATYPICAL ANTIPSYCHOTICS
If you are a pregnant woman between the ages of 18 and 45 and are currently treated with one or more of the following atypical antipsychotics:
- Abilify (aripiprazole)
- Clozaril (clozapine)
- Geodon (ziprasidone)
- Invega (paliperidone)
- Risperdal (risperidone)
- Seroquel (quetiapine)
- Zyprexa (olanzapine)
Register now by calling 1-866-961-2388 and help make the future better for many other women just like you…
This study will involve 3 brief phone interviews over an 8-month period.
The National Pregnancy Registry for Atypical Antipsychotics is dedicated to evaluating the safety of atypical antipsychotic medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in infants exposed to atypical antipsychotics during pregnancy.
For more information, please call 1-866-961-2388.
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 $350.
For information, please call: (617) 724-6540 or email afarrell2@partners.org
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.
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