Marlene P. Freeman, MD

Dr Freeman is a speaker at this year’s PsychCongress in a presentation titled “Menopausal Depression and Premenstrual Mood Dysregulation.”  

The menopausal transition is characterized by sex hormone variability and a vulnerability to depressive symptoms and major depressive episodes. The rate of new-onset major depressive episodes is increased during the menopausal transition, as is the experience of depressive symptoms. The majority of women suffer from hot flashes, or vasomotor symptoms, which range in severity from mild to more severe with an impact on functioning.

The term “perimenopause” refers to the time around this reproductive life cycle transition. More formally, the term “postmenopause” refers to the time 12 months or later after the final menses. Carefully conducted longitudinal studies have demonstrated that perimenopausal women are at 

 for major depressive episodes than are premenopausal women, and that the risk is associated with hormonal variability.

 It appears that it is not the absolute levels of sex hormones such as estrogen that confer risk, but rather the variability that characterizes the menopausal transition.

Common symptoms other than depression and hot flashes that psychiatrists may frequently encounter include sleep dysregulation, cognitive complaints, fatigue, pain, and anxiety. The symptoms that accompany the menopausal transition are explained by the “estrogen withdrawal theory.”

 This theory can be applied to explain vulnerabilities to depressive symptoms during reproductive hormone variability-premenstrually, postpartum, perimenopause, and at times of fluctuating levels of estrogen and other gonadal hormones.

While the life cycle transition of menopause is characterized by hormonal vulnerability, hormone treatment is not necessarily the only treatment, although it may be used as a primary or adjunctive strategy. Estrogen is known to diminish hot flashes, but the risk-benefit profile is in question, and many women seek to avoid hormone therapies. Notably, there was controversy around the routine use of hormone replacement therapy after the release of findings from the 

 This study showed that women who received estrogen plus progestin were at a slightly increased risk for coronary heart disease, stroke, pulmonary emboli, and invasive breast cancer. Further, they did not have the preventive health benefits that were widely believed to be associated with long-term hormone therapy.

A major depressive episode in the menopausal transition is treated similarly to an episode that may occur at any other time of life, with the caveat that antidepressants with serotonergic activity, particularly SSRIs and SNRIs, are also effective for the treatment of hot flashes.

 Other pharmacological strategies can be used to target hot flashes specifically, such as gabapentin.

 Sleep dysregulation associated with the menopausal transition can be specifically targeted with cognitive-behavioral strategies or medications to improve sleep, such as sedating antidepressants or hypnotics.

serves as a summary of indicators of menopausal transition and menopausal symptoms discussed in this article.

[[{"type":"media","view_mode":"media_crop","fid":"27444","attributes":{"alt":"","class":"media-image","id":"media_crop_7699358080711","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"2675","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","title":" ","typeof":"foaf:Image"}}]]Dr Freeman is Associate Professor of Psychiatry at Harvard Medical School; Medical Director of CTNI; Director of Clinical Services, Perinatal and Reproductive Psychiatry Program at Massachusetts General Hospital in Boston. She is the Depression Section Coeditor for 

with George I. Papakostas, MD. Dr Freeman reports that over the past 12 months she has served on advisory boards and/or consulted for Takeda, Lundbeck, Otsuka, Johnson & Johnson, Genentech, and JDS Therapeutics, and she has edited for DSM Nutritionals.

1. Cohen LS, Soares CN, Vitonis AF, et al. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. 

 2006;63:385-390.
2. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. 

 2006;63:375-382.
3. Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. 

 2000;183:414-420.
4. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. 

2002;288:321-333.
5. Soares CN, Frey BN. Challenges and opportunities to manage depression during the menopausal transition and beyond. 

 2010;33:295-308.
6. Pinkerton JV, Kagan R, Portman D, et al; Breeze 3 Investigators. Phase 3 randomized controlled study of gastroretentive gabapentin for the treatment of moderate-to-severe hot flashes in menopause. 

2014;21:567-573.
7. Joffe H, Massler A, Sharkey KM. Evaluation and management of sleep disturbance during the menopause transition. 

Articles

The menopausal transition is characterized by sex hormone variability and a vulnerability to depressive symptoms and major depressive episodes. The rate of new-onset major depressive episodes is increased during the menopausal transition, as is the experience of depressive symptoms. 

Psychiatry and the Menopausal Transition: Clinical Caveats

[[{"type":"media","view_mode":"media_crop","fid":"23388","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_1186427198504","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1832","media_crop_rotate":"0","media_crop_scale_h":"200","media_crop_scale_w":"159","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Mood disorders frequently have a chronic or recurrent course, and women with mood disorders typically experience the onset of these disorders before or during their reproductive years.

 Therefore, women commonly experience mood episodes during the perinatal period (during pregnancy and postpartum). Many women plan for a pregnancy with a preexisting mood disorder and while receiving maintenance treatment with psychotropic medication. Ideally, women plan ahead to conceive and make any necessary treatment changes to maximize wellness and minimize fetal medication exposure-especially to medications that are known teratogens or have unknown reproductive safety profiles.

However, about 50% of pregnancies in the US are unplanned. This fact underscores the need to routinely counsel women of reproductive potential about their medications, regardless of their plans to conceive.

 It is also of major importance to select medications for women of reproductive potential that would be of least risk should they experience an unplanned pregnancy.

The psychopharmacologist should actively inquire about a woman’s plans for conceiving. If a woman is not planning to become pregnant, contraception should be discussed routinely. If a woman is using hormonal contraception, such as an oral contraceptive, there are important potential drug actions to factor into medication dosing.

Many women who report that they are not trying to conceive are not using an effective contraceptive. One recent national study demonstrated that among young women, one-third were using the “withdrawal method” as their primary form of birth control. Among them, 21.4% experienced an unintended pregnancy.

Our role is 2-fold: we need to actively integrate patients’ desires for pregnancy into our treatment plans, but also extend the use of selective prescribing for women of reproductive potential regardless of stated plans.

The rate of congenital malformations in the general population of the US is approximately 3% of all pregnancies.

 Maternal age is a known risk factor for pregnancy complications and birth defects, as are smoking, alcohol use, uncontrolled diabetes, and obesity.

 In most cases, causes of birth defects are unknown. Decision making around treatments for psychiatric disorders in pregnancy requires consideration of what is known about the medications in pregnancy, the disorder being treated, and exposures to the baby of both untreated maternal illness and medication. For women of reproductive age planning pregnancy, the CDC recommends the following

• Take folic acid (higher doses are recommended when a woman is taking an anticonvulsant before trying to conceive

• Quit/abstain from tobacco use, alcohol, and drugs

• Communicate with health care professionals about screening for and management of chronic diseases

The CDC also recommends that sexually active women who wish to delay or avoid pregnancy should use effective contraception correctly.

Treatment considerations when planning for pregnancy

It is a major treatment dilemma when a woman decides to try to conceive or becomes pregnant while being treated with a particularly risky medication. A switch during pregnancy means that a woman will have more than one medication exposure during her pregnancy, and a trial of a med-ication that is new to her is complicated by the fact that the risk to benefit ratio for her is unknown. Therefore, the initial selection of psychotropics for women with psychiatric disorders should include consideration of reproductive potential and data regarding use in human pregnancy.

Unfortunately, it is challenging to remain apprised of data pertaining to medication use in pregnancy, since the literature is constantly evolving. For some medications, such as SSRIs, lamotrigine, and benzodiazepines, there are a great number of published studies-some with conflicting results.

 For other medications that are known teratogens, such as lithium and valproic acid, the association with birth defects is clear, but the absolute risk of teratogenicity must be understood to make informed decisions.

 With lithium, which has a known association with a specific cardiovascular malformation-Ebstein anomaly-the absolute risk is low. Approximately 0.1% to 0.2% of pregnancies are affected when there is exposure in the first trimester. In contrast, valproate has a known and common association with neural tube defect, estimated to occur in 1% to 5% of exposed pregnancies.

Unfortunately, the FDA pregnancy categories (A, B, C, D, X) are of limited use and can be misleading regarding what constitutes a relative risk of one medication compared with another when used in pregnancy.

 The risks of the untreated disorder also are not reflected in this system. Most psychotropic medications are labeled as C or D. The process of category labeling is as follows for a new drug: When a new drug comes to market, a letter is assigned and usually there is a paucity of human data at that point. Pharmaceutical companies are required to have a modest amount of animal data on hand. In general, however, there is no incentive for a company to have human pregnancy data at the time of approval. In fact, women who are pregnant or who are using inadequate methods of contraception are generally barred from participation in clinical trials.

This means that only postmarketing surveillance data are derived from pregnant women. Pregnant women are disqualified from randomized trials of psychotropic medications. Naturalistic studies are used, which must be interpreted with care to account for variables (including the underlying disorder, factors associated with the illness, and medication use) because groups of women receiving a particular medication may not be adequately matched with controls.

The effect of the FDA pregnancy categories is that some newer medications without human pregnancy data receive a relatively favorable category, such as “B,” while older medications that are well studied and may have a well characterized small risk or inconsistently reported risk may be labeled as “D.” However, it is possible-and common-that a drug in the “D” category would be preferable to one labeled “B,” especially when the older drug has received a great deal of study and has a very small absolute risk, and the newer drug labeled “B” is unknown in human pregnancy. The bottom line is that the FDA categories are seductive-they lead us to believe that the medications fall into clear and distinct categories, when in fact they rarely inform us about how to select medications for women.

In advance of a pregnancy, the following are guidelines to keep in mind

• Aim for remission before a pregnancy; encourage a period of wellness before conception

• Provide psychotherapy before a pregnancy

• Select the drugs that are most reasonable on the basis of the patient’s personal history of illness and treatment response (valproate is the most commonly used psychotropic agent with the highest risk of teratogenicity

• Minimize the number of drugs and doses while maintaining euthymia

• Arrange for careful monitoring of mood throughout pregnancy and the postpartum period

Pregnancy is inherently risky. Our goals are to decrease risks to and promote wellness for the mother and baby as much as possible. We are not able to state that any medication is absolutely “safe.” When initiating treatment with medications, keep in mind that unplanned pregnancies are common. The FDA pregnancy categories are extremely limited in clinical value. The risks of untreated disorders must be taken into account in terms of fetal and infant exposure. In this area with so many unknowns, collaborative decision making with the patient is essential.

Treating Mood Disorders in Young Women: Resources for Clinicians and Patients

• Massachusetts General Hospital Center for Women’s Mental Health: 

• Centers for Disease Control and Prevention: 

http://www.cdc.gov/reproductivehealth/unintendedpregnancy/contraception.htm

• Organization of Teratology Information Specialists (OTIS):


Dr Freeman is Associate Professor of Psychiatry at the Harvard Medical School; Medical Director, Clinical Trials Network and Institute; and Director of Clinical Services, Perinatal and Reproductive Psychiatry Program at the Massachusetts General Hospital in Boston. She has received research support from GSK and Lilly; is on the advisory boards of Lundbeck, Taleeda, Otsuka, and Genentech; and does medical editing for DSM Nutritional Products.

 Vesga-LÃ³pez O, Blanco C, Keyes K, et al. Psychiatric disorders in pregnant and postpartum women in the United States. 

 Finer LB, Zolna MR. Unintended pregnancy in the United States: incidence and disparities, 2006. 

 Gaffield ME, Culwell KR, Lee CR. The use of hormonal contraception among women taking anticonvulsant therapy. 

 Dude A, Neustadt A, Martins S, Gilliam M. Use of withdrawal and unintended pregnancy among females 15-24 years of age. 

 Centers for Disease Control and Prevention. National Center on Birth Defects and Developmental Disabilities. http://www.cdc.gov/ncbddd/aboutus/birthdefects-bd-maternal.html. Accessed November 27, 2013.

 Wilson RD, Johnson JA, Wyatt P, et al; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada; The Motherrisk Program. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. 

 Yonkers KA, Wisner KL, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. 

 Law R, Bozzo P, Koren G, Einarson A. FDA pregnancy risk categories and the CPS: do they help or are they a hindrance? 

 Center for Drug Evaluation and Research, US Department of Health, Education, and Welfare. Guidance for Industry: General Considerations for the Clinical Evaluation for Drugs. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm071682.pdf. Accessed November 28, 2013.

 Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. 

 Nguyen HT, Sharma V, McIntyre RS. Teratogenesis associated with antibipolar agents. 

Because half of pregnancies in this country are unplanned, it's crucial to counsel women of reproductive potential about their medications-regardless of their plans to conceive.

Author | Marlene P. Freeman, MD

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