Volume 6 Issue 2, September 2009

Dear Readers,

In this issue of the Women’s Mental Health Bulletin, the newsletter for the Massachusetts General Hospital Center for Women’s Mental Health, you will find information 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 screening for metabolic side effects in patients treated with atypical antipsychotic agents. We are seeing a growing number of patients treated with this class of drugs, and carefully monitoring for metabolic side effects, including weight gain, glucose dysregulation/diabetes, and dyslipidemia (elevated triglycerides and/or cholesterol). The Center is now enrolling patients in a new study which is designed to assess the efficacy of omega-3 fatty acids for reducing high triglyceride and/or high cholesterol levels in patients taking atypical antipsychotic drugs.

This issue also reviews preliminary data from a recent study from the Center which examines the various factors influencing individual decisions about continuing or discontinuing mood stabilizer treatment during pregnancy in women with bipolar disorder.

As always, thank you for your interest in our Program.

Ruta Nonacs, MD PhD
Editor-in-Chief

New Research: Treatment Decisions by Pregnant Women with Bipolar Disorder

Choosing whether to maintain or discontinue mood stabilizer treatment during pregnancy requires weighing the risks of teratogenic outcomes associated with exposure to a particular drug against the risks of recurrence of untreated affective illness. However, previous studies have suggested that decisions about psychotropic treatment during pregnancy appear to be largely independent of past illness severity or clinical recommendations (Viguera et al 2002, Bonari et al 2005).

A recent study from the MGH Center for Women’s Health aimed to examine factors influencing individual decisions about continuing or discontinuing mood stabilizer treatment during pregnancy in women with bipolar disorder.

Pregnant women (N=138) diagnosed with DSM-IV bipolar disorder (type I or II) completed a treatment preference questionnaire as part of a study of recurrence risk during pregnancy. Of these 138 women, 55 decided to maintain treatment with their mood stabilizer, 35 discontinued their mood stabilizer before conception, and 48 discontinued their mood stabilizer after conception. This study questionnaire required subjects to rank a list of reasons for their decision to continue or discontinue mood stabilizing treatment.

For women who chose to maintain their mood stabilizer, the top three reason were: anxiety about relapse (69.1%), physician advice (47.3%), and failed past discontinuation (40%). The top three reasons for women to discontinue their mood stabilizer before conception were: fear of the effect on baby (60%), considering illness not severe (17.1%), and opinion of partner/husband (14.3%). The top three reasons for women to discontinue their mood stabilizer after conception were: fear of effect on the baby (56.3%), opinion of family/friends (10%), and physician advice (8.3%).

In summary, the main determinant in decisions to continue maintenance mood stabilizer treatment was patient concern about risk of recurrence during pregnancy. Among women who decided to discontinue their mood stabilizer during pregnancy, concerns over potential fetal teratogenic risks superseded other determinants. These findings clarify factors associated with decisions about treatment during pregnancy by women with bipolar disorder, and suggest that clinicians carefully consider an individual patient’s concerns when discussing treatment options.

Rachel Vanderkruik, BA

Adele C. Viguera, MD, MPH

Vanderkruik R, Viguera AC, Whitfield TH, Baldessarini, Cohen LS. Treatment Decisions by Pregnant Women with Bipolar Disorder. Presented at the 2009 Annual Meeting of the American Psychiatric Association.

Viguera AC, Cohen LS, Bouffard S, Whitfield TH, Baldessarini RJ. Reproductive decisions by women with bipolar disorder after pre-pregnancy psychiatric consultation. Am J Psychiatry 2002; 159: 2102–2104.

Bonari L, Koren G, Einarson TR, Jasper JD, Taddio A, Einarson A. Use of antidepressants by pregnant women: evaluation of prediction of risk, efficacy of evidence-based counseling, and determinants of decision making. Arch Women’s Ment Health 2005; 8:214–220.

Screening for Metabolic Side Effects of Atypical Antipsychotic Drugs

Atypical antipsychotic drugs are increasingly used to treat psychiatric disorders such as bipolar disorder and schizophrenia. In spite of the important role they play in treating serious psychiatric disorders, atypicals have been associated with negative side effects, including weight gain, glucose dysregulation/diabetes, and dyslipidemia (elevated triglycerides/cholesterol).

Assessment Before Treatment. Balf et al (2008) describe the need for increased monitoring and management of these risk factors in patients treated with psychotropic drugs. Recommendations made by the Mount Sinai Conference and the American Diabetes Association (ADA) state that several parameters should be evaluated prior to initiating treatment with an atypical antipsychotic drug: family history of metabolic conditions, weight and height, waist circumference, plasma glucose level, blood pressure, and lipid profile.

Ongoing Monitoring. After these baseline assessments, it is suggested that weight and body mass index be checked every 3 months while taking an atypical. A body mass index increase of 1 unit, or a weight gain of >7%, is cause for concern. Similarly, monitoring for diabetes with a fasting plasma glucose level should be performed every 3-4 months. Fasting glucose levels of 100 mg/dL-125 mg/dL signify pre-diabetes and should be closely followed. A fasting lipid profile (including total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides) should be obtained at baseline and 3 months into treatment with an atypical, and then every 5 years, based on the American Diabetes Association and APA recommendations. The Mount Sinai guidelines suggest that routine monitoring of lipids be done more frequently, every 2 years.

Balf and colleagues also refer to the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Study, which found that many patients with schizophrenia discontinued their treatment due to weight gain. An added bonus to improved monitoring of such side effects is that patients may better adhere to treatment.

Marlene P. Freeman, MD

Rachel C. Vanderkruik, BA

We are now enrolling patients in a new study looking at omega-3 fatty acids for the treatment of high triglyceride and/or high cholesterol levels.

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.

American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27 (2): 596-601.

Balf G., Stewart T., Whitehead R., Baker R. Metabolic Adverse Events in Patients with Mental Illness Treated with Antipsychotics: A Primary Care Perspective. Prim Care Companion J Clin Psychiatry 2008; 10(1), 15-24.

Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353(12):1209-1223

Marder S, Essock S, Miller A, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161 (8): 1334-1349.

National Pregnancy Registry for Atypical Antipsychotics

We are pleased to announce the recent launch of the National Pregnancy Registry for Atypical Antipsychotics. We are currently enrolling participants from across the country from Massachusetts to Alaska.

The Registry represents the first hospital-based pregnancy registry for atypical antipsychotics in America. The aim of this research study is to systematically and prospectively evaluate fetal and maternal outcomes following use of these medications during pregnancy. Atypical antipsychotics are being increasingly used among women of child-bearing age as primary or adjunctive therapy across a wide range of psychiatric disorders, including bipolar disorder, schizophrenia, unipolar depression, anxiety disorders and other psychotic illnesses. Therefore, there is an urgent need for information regarding the reproductive safety for these medications.

Currently, there is no formal mandate from the U.S. Food and Drug Administration (FDA) that reproductive safety information be systematically collected, resulting in a literature that is often confusing and inconsistent in findings. 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. 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. Therefore, important drug safety information is not available to women who must often face the clinical dilemma of whether to continue or discontinue their medication during pregnancy.

Over the past decade, pregnancy registries have emerged as an effective and efficient method for collecting important reproductive safety data and the establishment of the National Pregnancy Registry for Atypical Antipsychotics is an important step in the collection of such important data. Pregnant women who have taken one or more atypical antipsychotics for any reason at any point in their pregnancy are eligible to enroll in the study. The medications being studied include: Abilify (aripiprazole), Clozaril (clozapine), Geodon (ziprasidone), Invega (paliperidone), Risperdal (risperidone), Seroquel (quetiapine), Zyprexa (olanzapine).

Participation in the Registry involves three brief phone interviews over a period of approximately 8 months, depending on where women are in their pregnancy when they enroll in the study. The phone interviews involve questions regarding maternal health and neonatal outcomes. In addition, we will request women’s obstetric, labor and delivery, neonatal and pediatric medical records. Women interested in participating in this study may contact us by phone (toll-free) at 1-866-961-2388 or by email at registry@womensmentalhealth.org.

The primary aim of the Registry is to estimate the frequency of major malformations such as heart defects, spina bifida, and cleft lip, in infants exposed to atypical antipsychotics. We are also interested in determining other possible risks associated from exposure to these medications during pregnancy including neonatal and maternal health outcomes. Major malformation rates among Registry participants will be compared to rates among women who are not exposed to atypical antipsychotics during pregnancy.

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 Viguera, MD

Stephanie Connors, BS

From Our Blog: Use of Complementary and Alternative Medicines for Menopausal Hot Flashes

Approximately seventy percent of all women experience hot flashes and/or night sweats (also called vasomotor symptoms) during the menopause transition (Stearns et al. 2002). Until recently, estrogen therapy was the treatment of choice for most women who sought treatment for hot flashes. Since the results of the Women’s Health Initiative in 2002 noted risks of prolonged use of hormone therapy in older postmenopausal women (Roussouw et al. 2002), many women pursue other treatments for their hot flashes, including over-the-counter complementary and alternative medicines (CAMs), including soy isoflavines, black cohosh, and omega-3 fatty acids. However, there is limited evidence to support the use of these treatments for hot flashes to date.

A recent report from the National Center for Complementary and Alternative Medicine (NCCAM) showed that over 40% of adults in the United States reported used at least one CAM treatment in the past 12 months, and women over the age of 40 were the largest group of CAM users (Barnes, 2008).

Soy Isoflavines and Phytoestrogens (e.g. soy beverages, soy supplements, flax seed). The effect of soy isoflavine extracts on hot flashes has been studied extensively, but most studies have found that they are no more effective than placebo. Recent reviews (Nedrow et al, 2006 and Nelson et al, 2006) of clinical trials using dietary sources of soy isoflavines (e.g., soy beverages, soy powder) and phytoestrogens (e.g., red clover supplements) have concluded that these treatments were not beneficial in 93% of the 30 studies reviewed. It is important to note that in many of the trials, hot flashes improved in both placebo and treatment groups, indicating high placebo response rates in these studies and making it difficult to distinguish between the beneficial effects of soy, placebo response, and non-specific effects of monitoring and study participation.

Black Cohosh. There have been five trials comparing black cohosh to no treatment or placebo for the treatment of hot flashes (Osmers et al, 2005; Jacobson et al, 2001; Newton et al, 2006; Hernandez and Pluchino, 2003; Wuttke et al, 2003). The studies used a range of doses from 20mg to 160mg per day. Four of these studies showed no improvement in the treatment group versus placebo. While one (Osmers et al. 2005) found that the group treated with black cohosh reported a decrease in hot flashes, black cohosh appeared to be most effective in a subset of women, those with recent onset of menopausal symptoms.

Omega-3 Fatty Acids. Omega-3 fatty acids have recently been examined as a possible treatment for hot flashes and are an appealing treatment option, as their safety and cardiovascular benefits are well-established.

The results from the first double-blind, placebo-controlled randomized clinical trial of ethyl-eicosapentaenoic acid (E-EPA), a type of omega-3 fatty acid are encouraging (Lucas et al., 2009). The investigators randomized 120 women to be treated with either 500mg of E-EPA three times a day or with placebo over an 8-week period and compared changes in hot flashes using a hot flash diary. The investigators found that E-EPA was more effective than placebo in reducing hot flashes, with a 55% average reduction in symptoms in the E-EPA group and a 25% average reduction in the placebo group. Women in the E-EPA group were three times more likely to experience a substantial improvement (>50% reduction in hot flashes) than those in the placebo group.

It is notable that study participants were selected because they experienced psychological distress and not because of hot flashes alone, although all of the women participating reported experiencing hot flashes. Depressive symptoms also improved with treatment in both groups. Therefore, it is not yet known whether women with hot flashes who do not have concurrent psychological distress will have a similar response to E-EPA.

In summary, studies of CAM for the treatment of menopause-related hot flashes have demonstrated that treatments such as soy and black cohosh are not likely to be effective in most women, while the study of omega-3 fatty acids is promising yet too preliminary to conclude definitively that omega-3 fatty acids are effective. More studies are needed to better assess the efficacy of omega-3 fatty acids in this population. Women and their clinicians should consider these results as well as potential side effects as they evaluate treatment approaches to managing bothersome hot flashes.

Erica Pasciullo, BA

Hadine Joffe, MD, MSc

Click here to read our previous blog post on phytoestrogens

Lucas et al. Effects of ethyl-eicosapentaenoic acid omega-3 fatty acid supplementation on hot flashes and quality of life among middle-aged women: a double-blind, placebo-controlled, randomized clinical trial. Menopause 2009; 16(2): [Epub ahead of print]

Stearns et al. Hot flushes. Lancet 2002; 360:1851-1861.

Nedrow et al. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Archives of Internal Medicine 2006 Jul 24;166(14):1453-65.

Nelson et al. Nonhormonal Therapies for Menopausal Hot Flashes: Systematic Review and Meta-Analysis. JAMA. 2006;295(17):2057-2071.

Barnes PM, et al. CDC National Health Statistics Report #12. Complementary and Alternative Medicine Use Among Adults and Children: United States, 2007. December 10, 2008.

We invite you to email us at admin@womensmentalhealth.org with topics that you would like to hear about on our blog!

New Research at the Center for Women’s Mental Health

MENOPAUSAL WOMEN WITH HOT FLASHES NEEDED FOR RESEARCH STUDY (New!)

Are you menopausal?

Do you have hot flashes?

If you are a 40-62 year-old menopausal woman who has hot flashes, you may be eligible for a 14-week research study at both Massachusetts General Hospital and Brigham and Women’s Hospital evaluating how an antidepressant medication treats your menopausal symptoms. You will receive study medication and monitoring of your menopausal symptoms at no cost. You will be compensated up to $180 for your participation.

If you are interested in this study and would like to be seen at Massachusetts General Hospital:

Please call (617) 724-6540 or email MGH@MsFlash.org

185 Cambridge Street, Suite 2000

Boston, MA 02114

If you are interested in this study and would like to be seen at Brigham and Women’s Hospital:

Please call (617) 732-9863 or email BWH@MsFlash.org

850 Boylston Street, Suite 307
Chesnut Hill, MA 02467

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 sfowler@partners.org

Ongoing Research at the Center for Women’s Mental Health

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)

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.

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 sdconnors@partners.org

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 aheberle@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? The Center for Women’s Mental Health at Massachusetts General Hospital is conducting a research study on Bipolar Disorder in 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 contact Suzanna at (617) 726-2912.

Mass General Hospital

Center for Women's Mental Health