CHAPTER 38

Treatment of Women

Vivien K. Burt, M.D., Ph.D.

Rita Suri, M.D.

Carole Edelstein, M.D.

Although overall men and women are at equal risk for developing a psychiatric disorder over their lifetime, there are gender-specific differences in the prevalence and clinical course of a number of specific mental disorders. These differences stem from a variety of factors, including biological and experiential differences between the sexes. Probably due in part to genetically primed alterations in the risk of depression in response to changing hormones during the menstrual cycle, pregnancy, and the postpartum period, the heritability of major depressive disorder appears to be higher in women than in men (Kendler et al. 2006). These female-specific hormonal and physiological differences predispose women to certain psychiatric illnesses and inform treatment decisions.

Table 38-1 lists reproductive-related times that may influence the onset, course, and treatment of psychiatric disorders in women. Each of these times or transitional events presents hormonal challenges that have potential consequences in women's moods, behavior, and thought processing. For some vulnerable women, these reproductive transitions are times of great psychosocial stress that further increase the risk for depression and anxiety. In some cases, endogenous hormones (e.g., thyroid hormone, estrogen, progesterone) and exogenous hormones (e.g., found in contraceptives, postmenopausal hormone treatment, fertility medications) influence the psychiatric states of women. Furthermore, because more than 50% of pregnancies in the United States are unplanned, the psychiatric evaluation of reproductive-age women should always include questions about sexual activity, use and form of birth control, history of unprotected intercourse, recent missed periods, and regularity of menstrual cycles. Because current and past depression may be associated with earlier decline in ovarian function, women with depression who plan to become pregnant in their 30s or early 40s should be treated robustly and to full remission (Harlow et al. 2003).

A variety of factors—including gender-specific differences in drug absorption, bioavailability, metabolism, and elimination—influence how women respond to psychotropic medications. The net effect of these factors is that compared with men, women tend to have greater bioavailability and slower clearance of drugs, such that optimal dosages for men may be too high for women. Furthermore, women tend to be taking more medications than men and are more prone to side effects associated with drug-drug interactions.

The mental health needs of women are impacted by medical, social, and developmental history. Women with chronic medical illnesses (e.g., diabetes, epilepsy, thyroid disorders, fibromyalgia) are at increased risk for mood and anxiety disorders. Sexual preference, relationship styles, current state of relationships, and emotional, physical, or sexual abuse may inform clinicians about which treatment option is most likely to be efficacious. Often, women with histories of major mental illnesses pair with partners with psychiatric disorders. Thus, the risk of child behavior problems increases with the extent of psychological and social difficulties experienced by mothers (mental health, substance use, domestic violence). Psychiatric disorders independently and in association with psychosocial stressors therefore affect not only the well-being of mothers but also the emotional health of their children and the stability of their families (Table 38-2). Because women tend to display strong affiliative styles in their social relationships, dysfunctional relationships as well as psychiatric illness impact women of all ages, regardless of whether they have children.

Premenstrual Dysphoric Disorder

In DSM-IV-TR (American Psychiatric Association 2000), premenstrual dysphoric disorder (PMDD) was listed in Appendix B, "Criteria Sets and Axes Provided for Further Study." This condition comprises recurrent physical and emotional symptoms that begin in the late luteal phase of the menstrual cycle and remit within several days following the onset of menstruation. In addition to experiencing physical symptoms (bloating, breast tenderness, cramping, and headaches), the individual with PMDD has emotional symptoms that may include depression, irritability, anxiety, and insomnia. A panel of experts in women's mental health appointed by the DSM-5 Mood Disorders Work Group (Epperson et al. 2012) recommended that PMDD be moved from the DSM-IV-TR Appendix B to a formal categorical entity in the depressive disorders diagnostic class of DSM-5 (American Psychiatric Association 2013). Changes to the DSM-IV-TR criteria are relatively minor and meant to refine the research criteria. DSM-5 criteria state that symptoms must be present during the premenstrual week, rather than needing to be present most of the premenstrual week, and place greater emphasis on affective lability, irritability, and anger. Because women with PMDD often compensate and cope during their symptomatic days, the new criteria indicate that PMDD causes clinically significant distress or interferes with activities. New criteria also specify that the condition may co-occur with other disorders. There is also an additional Criterion G, which highlights the distinctiveness of PMDD from an ongoing medical condition or substance-induced condition. The DSM-5 diagnostic criteria for PMDD appear in Box 38-1.

Although documenting prospective daily symptom ratings over a 2-month interval is the most accurate way to establish the diagnosis, PMDD is frequently diagnosed provisionally, and treatment commences while prospective daily ratings are in progress. PMDD should be differentiated from the more common premenstrual syndrome (PMS), consisting of premenstrual bloating, breast tenderness, and mild psychological discomfort. Although such relatively mild premenstrual symptoms are experienced by up to 75% of reproductive-age women during at least some of their cycles (Steiner et al. 2006), only 2%-8% of women meet full criteria for PMDD as defined by DSM-TV-TR (Bailer et al. 2013). Because irritability, anger, dysphoria, and mood lability are common to a variety of psychiatric disorders, other psychiatric conditions should be ruled out as the primary cause for presenting complaints, because treatment approaches for PMDD may exacerbate or precipitate other psychiatric illnesses (e.g., bipolar disorder).

Evaluation for PMDD includes documentation of the course and nature of symptoms, possible precipitants, and prior treatment approaches and responses. Although by definition PMDD occurs during the luteal phase of the menstrual cycle, no consistent hormonal differences have been established in women with premenstrual emotional and physical symptoms. Physical conditions that may cause symptoms in association with the premenstrual phase of the menstrual cycle (e.g., endometriosis, fibrocystic breast disease, migraine headaches) should be ruled out. Because premenstrual symptoms tend to be familial, assessment should include a family history of premenstrual symptoms and effective treatments. Over-the-counter and prescription medications should be noted, and possible psychiatric side effects of these substances should be considered. The use of caffeine, salt, alcohol, and nicotine should be ascertained, because these may cause symptoms that mimic those of PMDD (e.g., bloating, lethargy, irritability, breast tenderness). A good psychosocial history is important as well, because an association of PMDD with stressful life events and also with past sexual abuse has been noted.

Mild premenstrual symptoms may be responsive to nonpharmacological interventions, such as sleep hygiene education, exercise, relaxation therapy, and cognitive-behavioral therapy. Dietary modifications, including reduction of salty foods, caffeine, red meat, and alcohol, along with increased consumption of fruits, legumes, whole grains, and water and consumption of smaller and more frequent meals high in carbohydrates have been reported to improve tension and depression. Documentation of daily prospective ratings often alerts the patient to high-risk times during which it is best to avoid difficult decisions. Such nonpharmacological interventions are useful to address symptoms while awaiting the results of prospective symptom ratings.

Because calcium (not exceeding 1,500 mg/day) and vitamin D may reduce the risk of moderate to severe premenstrual symptoms, and also may reduce the risk of osteoporosis and have other health advantages, women should be encouraged to include these in their daily diets.

The depression of PMDD is frequently as severe as that of major depressive disorder, and although PMDD symptoms occur solely during the luteal phase, the condition recurs monthly over years, often resulting in severe suffering and dysfunction. Fortunately, about 70% of women with moderate to severe PMDD respond robustly to definitive psychopharmacological care with selective serotonin reuptake inhibitors (SSRIs) (Yonkers et al. 2006). SSRIs are often given throughout the month, although administration only during the 2 premenstrual weeks (i.e., the luteal phase) has also met with success (e.g., Steiner et al. 2006). Treatment with an SSRI when symptoms begin until the onset of menses may also be effective, but larger studies are needed to confirm these data (Yonkers et al. 2006). Continuous pharmacological treatment (i.e., throughout the month) is best for women who have comorbid depressive or anxiety disorders or for women who tend to be incompletely compliant to intermittent therapy. Intermittent treatment with SSRIs is best for patients who have symptoms that are clearly localized to the premenstrual days and who may have side effects (e.g., sexual side effects) that dissipate on days when SSRIs are not used. Premenstrual anxiety and irritability may be treated with anxiolytics such as buspirone and alprazolam.

Psychiatric Disorders in Pregnancy

Pregnancy is not necessarily a time of emotional stability, particularly if the expectant mother has a prior history of psychiatric conditions or has changed or discontinued a medication regimen that had kept her stable and functional (Cohen et al. 2006; Flynn et al. 2006; Haas et al. 2011). Most pregnant women with current major depressive symptoms are either untreated or undertreated (Flynn et al. 2006). The best time for women with psychiatric histories to decide among possible treatment options during pregnancy is prior to becoming pregnant. In this way, a treatment algorithm can be formulated that maximizes safety and well-being for both patient and fetus. If clinically feasible, discontinuation of psychiatric medications should be considered. However, in some cases this is not best, because past history has shown that dose reduction or discontinuation of medication results in serious relapse, or because the patient is not fully stabilized even when provided with a comprehensive treatment regimen including psychotherapy and psychotropic medication.

Nonpharmacological interventions may not be sufficient during pregnancy, because unmedicated women with serious mood, anxiety, or psychotic disorders are often unable to care for themselves properly or to adhere to prenatal regimens. Psychiatric decompensation during pregnancy increases the risk not only of difficulties for the mother but also of obstetrical complications and adverse fetal outcomes (e.g., preeclampsia, placental abnormalities, low birth weight, preterm labor, fetal distress) (Chung et al. 2001; Evans et al. 2001; Federenko and Wadwha 2004; Kurki et al. 2000; Wisner et al. 2009). Furthermore, antenatal psychiatric instability increases the risk for illness during the postpartum period, when maternal responsibilities are new and particularly overwhelming. Patients should be advised that nicotine and alcohol are detrimental to the fetus and their own well-being, and strategies should be devised to ensure the opportunity for adequate sleep and healthful nutrition. Psychotherapy, group support, and family and marital counseling may be helpful, because pregnancy is a stressful time and may be particularly challenging for psychiatrically ill women, who often are so overwhelmed that they tend to decompensate during times of transition. When indicated, psychotropic medications during pregnancy are administered in order to prevent a relapse.

Before a psychotropic agent is administered to a pregnant patient, the risks and benefits to both the mother and the fetus should be evaluated and shared with the patient, her partner (whenever possible), and her obstetrician. The patient and her partner should be informed that the U.S. Food and Drug Administration (FDA) and the American Medical Association agree that although the FDA does not endorse the safety of any psychiatric medication in pregnancy, physicians may prescribe medications according to data-based knowledge and their own best clinical judgment. Pregnancy counseling should emphasize that the goal is to weigh any risk associated with maternal treatment using medications against known risks of untreated disease for mother and baby, during both pregnancy and the postpartum period. Discussions should be documented, and the clinician should assess and note the patient's understanding and capacity to consent to the treatment plan.

Table 38-3 presents general guiding principles for the treatment of psychiatric illness during pregnancy.

Treatment of Depression During Pregnancy

Studies have shown that rates of depression are greater at 32 weeks' gestation than at 8 weeks' postpartum (Evans et al. 2001) and that symptoms of depression affect 20% of pregnant women (Marcus et al. 2003). However, depression may be overlooked during pregnancy because many of the neurovegetative symptoms of depression coincide with normative somatic complaints of pregnancy. The functional impairment that frequently occurs in association with depression is of particular concern during pregnancy, because it tends to affect the health of both the expectant mother and her fetus. Furthermore, depression during pregnancy significantly increases the risk for postpartum depression. For mild to moderate depression, nonpharmacological modalities such as individual or conjoint psychotherapy and stress-reduction counseling are good first options for treatment. However, for severe and treatment-resistant depression, particularly if symptoms jeopardize a patient's emotional stability and the viability of the pregnancy (e.g., if the woman is suicidal, psychotic, or not gaining weight or is reluctantly contemplating an abortion), psychopharmacological approaches to treatment are reasonable.

Because the use of antidepressants during pregnancy is not without some risk, these medications should be withheld if possible. Bright light therapy is a noninvasive treatment option for antenatal depression. In addition to promoting fetal neurodevelopment and reducing the risk of preterm labor, omega-3 polyunsaturated fatty acids have also been suggested as a treatment for depression during pregnancy (Chiu et al. 2003). However, if a woman is experiencing severe, debilitating depression or if she has a history of chronic depression with severe relapses following medication discontinuation, antidepressants should be considered. When antidepressants are used during pregnancy, dosages should be kept at the minimum necessary to promote ongoing mood stability and normal functioning. The major issues of concern when evaluating outcomes with any medications in pregnancy, and in this case with antidepressants, are risks of congenital malformation, pregnancy loss, perinatal toxicity, length of gestation, and neurobehavioral sequelae.

An enormous amount of controversy exists regarding the risks and benefits of antidepressants in pregnancy, largely because studies in pregnant women are notoriously difficult to do. Therefore, the field is far from establishing definitive conclusions about absolute and relative risks for both maternal and infant outcomes. Among the many problems that make conclusions extremely difficult are inadequate randomization; lack of adequate controls; failure to address con-founders (e.g., the effect of depression, anxiety, or genetic loading on infant outcomes; the use of multiple medications; the use of illicit drugs and alcohol); use of administrative databases to establish data regarding diagnoses rather than establishment of actual intake of medications studied; and lack of blinding to cases and controls. Because women often are undertreated in pregnancy due to concerns about fetal outcome, it may well be that current use of a particular antidepressant or other psychotropic agent may be a better indication of acute illness during pregnancy than prior psychiatric history or an administrative note by a nonpsychiatric clinician. Thus, although absolute conclusions about risks in pregnancy for individual psychiatric medications are not possible, clinicians should be aware of accruing data for individual medications and classes of agents in order to help women and their partners make informed decisions regarding the treatment of depression during pregnancy.

Many women with severe major depressive disorder or anxiety disorders are symptomatic and dysfunctional during or just prior to pregnancy They may experience ongoing suicidal ideation (frequently passive, but deeply troubling), and some choose to abort their fetuses because they cannot remain off the medications that keep them free of disabling symptoms. Some women with serious depressive histories have become so alarmed by the literature suggesting that antidepressants are harmful agents in pregnancy that they have discontinued their antidepressants, experienced recurrences, and required restabilization with antidepressants in order to regain their health during the remainder of their pregnancies (Cohen et al. 2006). In the following subsections, which emphasize data from peer-reviewed studies, we review what is currently known about the use of antidepressants in pregnancy. Because SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the antidepressants most widely used to treat depression, and because of the large amount of conflicting, controversial, and sometimes alarming data published on the subject of SSRI use during pregnancy, the discussion below emphasizes the prenatal use of these agents.

Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors

Teratogenicity

Although numerous recent peer-reviewed studies on the use of SSRIs in pregnancy have found no significantly increased risk of birth defects (Einarson et al. 2009; Nordeng et al. 2012; Wichman et al. 2009), several other recent studies have suggested possible teratogenicity with in utero exposure to SSRIs (Alwan et al. 2007; Jimenez-Solem et al. 2012; Louik et al. 2007; Malm et al. 2011). Studies finding increased risks have been compromised by reliance on prescription data, lack of control for underlying psychiatric condition, low numbers of exposed subjects, low background absolute risk for uncommon defects, and inadequate control for substance and alcohol use or abuse. Thus, it has been estimated that although the risk for certain rare congenital malformations may be increased by a factor of 2 or 3, the absolute risk for such defects is very low—probably no more than 1 in 2,500 births. Paroxetine may be associated with cardiac defects (especially right-ventricle defects) of 1-2 per 100 infants (Cole et al. 2007; Källén and Otterblad Olausson 2007). It should be noted that any pregnancy carries about a 3% risk of having a birth defect, regardless of exposure, and that maternal stress and depression during pregnancy has also been associated with adverse reproductive outcomes (Alwan et al. 2007). Thus, as noted in a New England Journal of Medicine editorial, although it is impossible to delineate definitively either "no risk" or "risk" with most SSRIs (or most other medications) in pregnancy, "any increased risks of malformations in association with the use of SSRIs are likely to be small in terms of absolute risk" (Greene 2007, p. 2733).

Poor Neonatal Adaptability and Persistent Pulmonary Hypertension of the Newborn

Third-trimester exposure to SSRIs is associated with an increased risk of perinatal symptoms (including jitteriness, poor muscle tone, weak or absent cry, respiratory distress, hypoglycemia, low Apgar score, and seizures) that sometimes require admission to special care nurseries (Chambers et al. 2006). If infants have these symptoms, they are usually mild and disappear by age 2 weeks, and by age 4-5 years, these children seem to have no difference in mood or other behaviors (Misri et al. 2006). Late exposure to SSRIs may also increase the risk for persistent pulmonary hypertension of the newborn (PPHN) (Chambers et al. 2006). A case-control study (Wilson et al. 2011) found that cesarean delivery, but not SSRI exposure in the second half of pregnancy, increased the risk for PPHN. In December 2011 the FDA issued a public safety announcement advising health care professionals not to alter their current clinical practice of treating depression during pregnancy, stating that it is "premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN" (U.S.Food and Drug Administration 2011). Nevertheless, women exposed to an SSRI (or SNRI) late in pregnancy should be informed of this reported potential association.

Length of Gestation, Birth Weight, and Fetal Growth

SSRIs may be associated with an increased risk for shorter gestation (possibly preterm birth), small-for-gestational-age babies, and admission to special care nurseries (El Marroun et al. 2012; Suri et al. 2007; Wisner et al. 2009); however, birth weight and Apgar scores were not adversely affected by antidepressant use (Suri et al. 2007; Wisner et al. 2009). A large-scale prospective study (El Marroun et al. 2012) found that prenatal depressive symptoms were associated with reduced body growth and head growth, whereas prenatal SSRI use was associated with reduced fetal head growth, although the authors emphasized that this did not necessarily mean that antenatal SSRIs are associated with future developmental problems. A recent large systematic review and metaanalysis of pregnancy and delivery outcomes after prenatal exposure to antidepressants (Ross et al. 2013) found statistically but not clinically significant decreases in length of gestation (3 fewer days), birth weight (75 grams lower), and Apgar scores (less than half a point on the 1- and 5-minute scores). In summary, although length of gestation, birth weight, and fetal growth may be somewhat decreased with prenatal antidepressant exposure, the differences appear to be clinically insignificant, and Apgar scores, which measure the condition of neonates on delivery, are not clinically significantly different.

Neurobehavioral Sequelae

The developmental outcomes of children exposed to antidepressants in utero have been evaluated in a number of studies. Numerous studies have found no adverse developmental outcomes in children exposed antenatally to SSRIs (Nul-man et al. 1997, 2002; Suri et al. 2011). However, two articles have reported an association between autism spectrum disorder (ASD) and maternal use of antidepressants during pregnancy (SSRIs only: Croen et al. 2011; SSRIs and other antidepressants: Rai et al. 2013). If the association suggested in these studies is real, from 0.6% to about 2.3% of ASD cases could be attributable to first-trimester antidepressant exposure. In the study by Croen et al. (2011), mothers' previous history of mood and anxiety disorders was included in the analyses but acute ongoing mental illness during pregnancy was not factored in, thus diminishing the value of the data to assess the impact of actual prenatal SSRI use on the risk of autism. In the second study, by Rai et al. (2013), women with a history of depression who took antidepressants antenatally showed a small increased risk of having an infant with ASD without intellectual impairment, whereas women with such a history who did not take antidepressants during pregnancy showed no increased risk of this outcome; however, women who took antidepressants were more likely to be ill than those who did not. Furthermore, because many women who take antidepressants during pregnancy try to minimize their medication dosage, their depression may often be undertreated, resulting in dual exposure to the fetus—both to medication and to actual (often serious) psychiatric illness. A recently published large population-based cohort study that controlled for important confounding factors, including confounding by the underlying maternal indication for antidepressant use, found no significant association between prenatal exposure to antidepressant medication and ASD in the offspring (Sørensen et al. 2013). It therefore appears that antidepressant exposure in pregnancy is very unlikely to be a major risk factor for ASD and does not account for the increased rate of ASD in the general population. As always, the potential risk of medication exposure must be balanced against the risk to the mother or fetus of untreated mental illness.

A prospective study found that both antenatal depression and SSRIs affect brain plasticity, as reflected by developmental course of language discrimination (Weikum et al. 2012). Exposure to SSRIs and maternal depression during gestation appeared to have an impact on the timing and precision of speech perception, with SSRI exposure accelerating speech perception development, and untreated depression delaying this process. Further emphasizing the conundrum of whether and how to treat depression during pregnancy, the authors of this study suggest that because language development progresses on a finely tuned schedule, the impact of any change in such a schedule is not a desirable outcome.

Summary Regarding Use of SSRIs and SNRIs During Pregnancy

As noted in an important editorial on the use of antidepressant medication during pregnancy (Rubinow 2006), the treatment of depression during pregnancy presents the clinician and patient with difficult decisions. Depression during pregnancy is a very real and troubling problem, and the data regarding antidepressant use are limited and conflicting (some worrisome, some reassuring). Maternal depression clearly is a risk factor for affective and other difficulties in offspring. Although there may be a small increased risk for other rare congenital defects with SSRIs, the absolute risk is very small. Transient difficulties with neonatal adaptation must not be assumed to mean long-term difficulties, especially in the context of worsening maternal depression. The possibility of neurobehavioral and other long-term outcomes with in utero SSRI exposure and/or maternal depression and anxiety is at this point a subject of study. What is apparent is that for women with very troubling, impairing, and disabling depression and anxiety, nontreatment during pregnancy is not a feasible option.

Other Antidepressant Classes

Table 38-4 presents major summary points about the antenatal use of SSRIs, SNRIs, and other antidepressant classes.

Note. MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake inhibitor; TCA=tricyclic antidepressant.

Treatment of Bipolar Disorder During Pregnancy

Pregnancy does not protect against bipolar mood instability when mood stabilizers are discontinued (Sharma and Pope 2012). Rapid rather than gradual antepartum discontinuation of lithium increases the risk for postpartum relapse. Predictors of recurrence include antidepressant use and treatment discontinuation, younger age, illness onset at an earlier age, prenatal mood episodes, and somatic complaints during pregnancy.

The risks of teratogenicity associated with use of psychotropics during the first trimester must be carefully weighed against the risks of untreated bipolar disorder to the mother and fetus. With first-trimester use of lithium, the incidence of Ebstein's anomaly, a serious congenital defect in the formation of the tricuspid valve of the heart, is raised from the estimated rate of 1 per 20,000 in the general population to about 1 per 1,000. Additional potential adverse consequences to the neonate from maternal lithium use in pregnancy include rare transient perinatal effects (see Table 38-7 later in the chapter). In utero lithium exposure does not incur adverse neurobehavioral effects (van der Lugt et al. 2012).

First-trimester exposure to either valproate or carbamazepine increases the risk for neural tube defects, including spina bifida (up to 5% for valproate and 1% for carbamazepine), developmental delay, craniofacial defects, and other malformations. Of the conventional mood stabilizers, valproate carries the highest risk for major malformations, including significant developmental delay (Meador et al. 2012), atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis (Jentink et al. 2010). Cognitive deficits have been shown to persist up to 4.5 years (Meador et al. 2012). If exposure has occurred, an amniotic α-feto-protein analysis at week 16 and an ultrasound between weeks 18 and 22 should be obtained to assess for neural tube defects.

Although the North American Antiepileptic Drug Pregnancy Registry has suggested that lamotrigine monotherapy during the first trimester is associated with oral clefts (8.9 per 1,000 vs. 0.37 per 1,000 in the general population) (Holmes et al. 2006), this finding was not substantiated by data derived from the EUROCAT congenital malformation registries, representing 3.9 million births (Dolk et al. 2008). Even if there is an association between antenatal lamotrigine exposure and oral clefts, the absolute risk of having a child with an oral cleft is about 0.7%, a risk that bipolar women who are stable on lamotrigine may be willing to take when compared with adverse outcomes associated with bipolar relapse during pregnancy.

Because topiramate increases the risk for congenital malformations (especially oral clefts) and growth retardation in infants exposed in utero (Holmes and Hernandez-Diaz 2012), the medication should be avoided in pregnancy. The risk of malformations is significantly increased among infants exposed to valproate combined with either lamotrigine or carbamazepine (Holmes et al. 2011). Table 38-5 summarizes the risks of commonly used mood stabilizers in pregnancy.

Antipsychotics are sometimes used during pregnancy. Although low-potency phenothiazines may increase the risk of nonspecific congenital anomalies, high-potency antipsychotics have not been associated with major malformations. Atypical antipsychotics (olanzapine, risperidone, quetiapine, and clozapine) have not been shown to be teratogenic, but more controlled studies are needed to establish that these agents are safe in pregnancy. Quetiapine has the lowest placental passage rate (24.1%), whereas olanzapine has the highest placental passage rate (72.1%) and may result in a risk of low birth weight and neonatal intensive care admissions (Newport et al. 2007). Of particular concern during pregnancy is the risk of atypical antipsychotic-induced hyperglycemia and gestational diabetes (Bóden et al. 2012).

For infants exposed to traditional antipsychotic agents in utero near the time of delivery, a transient syndrome of motor restlessness, tremor, hypertonia, and poor feeding has been noted. Antipsychotic exposure in pregnancy has been associated with lower scores on tests of neuromotor performance, at age 6 months, although the extent of the relative contribution of underlying maternal mental illness is unclear and it is not known if these findings have any long-term clinical significance (Johnson et al. 2012).

Table 38-6 outlines some basic principles of managing bipolar disorder during pregnancy. In cases where long periods of interepisode euthymia have been demonstrated, an attempt may be made in advance of conception to avoid mood stabilizers during the first trimester. Careful tapering may be attempted over a period of 2-4 weeks to reduce the likelihood of relapse. However, for women who have historically been unable to remain stable without pharmacotherapy, medication is best continued throughout pregnancy. Lithium is preferable to carbamazepine and valproate because of its lower risk of teratogenicity. Guidelines for managing lithium in the bipolar pregnant woman are presented in Table 38-7.

Treatment of Schizophrenia During Pregnancy

Although some women with schizophrenia remain stable during pregnancy, others are at increased risk for poor prenatal care and adverse pregnancy outcomes (Jablensky et al. 2005; Matevosyan 2011). Patients should be screened for substance abuse, psychosocial stressors, housing and financial resources, and other factors that negatively affect parenting ability. Women with schizophrenia are more likely to have low dietary folate intake and to be obese (Connolly and Kelly 2005); therefore, they are at increased risk of having a child with a neural tube defect. Psychosocial support should be maximized to enhance proper nourishment, compliance with prenatal instructions (including daily intake of vitamins and folate), preparation for the responsibilities of motherhood, location of appropriate housing, and access to social services.

Source. Adapted from Newport DJ, Viguera AL, Beach AJ, et al: "Lithium Placental Passage and Obstetrical Outcome: Implications for Clinical Management During Late Pregnancy." American Journal of Psychiatry 162:2162-2170, 2005.

Antipsychotic medications should be used in pregnancy when necessary. The limited data on these medications in pregnancy were detailed in the previous section on bipolar disorder. The anticholinergic agents trihexyphenidyl and benztropine have been associated with minor congenital malformations and anticholinergic symptoms in the newborn, including functional bowel obstruction and urinary retention. Diphenhydramine does not appear to increase the risk of congenital malformations. Animal studies have reported cardiovascular malformations following in utero exposure to amantadine.

Table 38-8 summarizes the risks associated with the use of antipsychotics in pregnancy. Some (Bóden et al. 2012; Newham et al. 2008; Reis and Källén 2008) but not all (Lin et al. 2010) studies raise a concern for potential effects on fetal growth (birth weight, birth length, head circumference) and the risk of gestational diabetes.

Treatment of Anxiety or Obsessive-Compulsive Disorders During Pregnancy

The course of panic disorder, generalized anxiety disorder, or obsessive-compulsive disorder in pregnancy is variable. Discontinuation of anxiolytic antidepressants and other medications at the onset of pregnancy often results in relapse. Stress and anxiety in pregnancy increase the risk for maternal self-neglect, postpartum exacerbation, and cognitive, behavioral, and emotional alterations in babies and children (Gutteling et al. 2006; Hosseini et al. 2009; Hunter et al. 2012; Khashan et al. 2008; Kinney et al. 2008; Van den Bergh et al. 2005, 2008).

Nonpharmacological interventions for anxiety disorders include cognitive-behavioral therapy, elimination of caffeine and nicotine, reduction of psychosocial stressors, and couples therapy. Tricyclic antidepressants (TCAs) and SSRIs are reasonable treatment options for severe intractable symptoms that do not respond to those measures. For obsessive-compulsive disorder, SSRI dosages generally are higher than for treatment of depression. For severely anxious pregnant women, particularly as an SSRI begins to take effect, occasional small doses of benzodiazepines may be necessary. Intermittent use of low doses of benzodiazepines during pregnancy, particularly after the first trimester, does not appear to increase the risk of adverse neonatal sequelae. Nevertheless, the use of benzodiazepines in pregnancy is controversial, with some researchers noting a risk of oral clefts, particularly with diazepam and alprazolam. Thus, an attempt should be made to avoid benzodiazepines during gestational weeks 5-9, because this is when formation of the fetal palate occurs. Of the benzodiazepines, lorazepam is a reasonable choice, because it has no active metabolites and passes into the placenta at a lower rate than do other benzodiazepines. Transient perinatal syndromes, including hypotonia, failure to feed, temperature dysregulation, apnea, and low Apgar scores, have been noted with last-trimester use of benzodiazepines. Near term, benzodiazepines should generally be kept at a minimum. Whenever possible, benzodiazepine dosage changes should be gradual, to avoid precipitating in utero withdrawal.

Use of Electroconvulsive Therapy During Pregnancy

Electroconvulsive therapy (ECT) is feasible for pregnant patients with severe mood disorders because it appears safe and effective and exposes the developing fetus to a minimum of psychoactive medication (Miller 1994). Special considerations in the administration of ECT to pregnant women include the need for a pelvic examination and uterine tocodynamometry to exclude uterine contractions and elevation of the right hip to ensure adequate placental perfusion. The muscle relaxant succinylcholine and the anticholinergic agent glycopyrrolate appear relatively safe to use in pregnancy (Miller 1994). Propofol and methohexital sodium, the most frequently used anesthetic agents for ECT in the United States, are both short acting and have not been associated with teratogenicity. Given the potential for fetal sedation, obstetric fetal monitoring during ECT is necessary. Following the procedure, external fetal monitoring should continue for several hours. Treatment response rates for pregnant women with depression and schizophrenia have been found to be comparable to those for nonpregnant subjects (Anderson and Reti 2009), and ECT may be a reasonable option for pregnant women with severe symptoms, including psychotic catatonia or strong suicidality.

Postpartum Psychiatric Disorders

The 6 months following delivery is a time of increased risk for emotional instability for many women. Conditions of disordered mood occurring following childbirth include postpartum blues, postpartum depression, and postpartum psychosis. The postpartum period is also a time of recurrent and new-onset anxiety disorders. Although no specific etiology has been found to explain the onset of psychiatric illness during the postpartum period, the causes probably reside in a combination of biological/endocrinological and psychosocial factors. Because the data on postpartum anxiety disorders are sparse, our discussion on postpartum conditions focuses mainly on postpartum mood disorders. Increased risks for the emergence of major mood disorders occur in the postpartum period for women diagnosed with either unipolar or bipolar mood disorders, and are higher for bipolar disorder than for unipolar depression (Viguera et al. 2011). Major depressive disorder is the most common form of perinatal mood disorder, whether patients had histories of unipolar or bipolar affective illness.

Table 38-9 summarizes the three mood disorders that occur in the postpartum period, their presentation, and treatment considerations.

Postpartum Depression

Major postpartum depression occurs at a rate of 12%-13%, equaling that in the general female population. However, the rate of troubling depression not meeting full criteria for major depressive disorder appears to be much higher. Although the first postpartum year is a time of high risk for emergent mood disorders, the first 3 months postpartum represent a particularly heightened risk (Munk-Olsen et al. 2009). Nevertheless, the "postpartum onset" specifier in DSM-IV-TR may be applied only for depression (unipolar, bipolar I or II) with onset in the first 4 weeks after childbirth. Risk factors for postpartum depression include previous postpartum depression, a history of depression, family history of mood disorders, stressful life events, poor social support, and low self-esteem. Endocrine risk factors, including elevated mid-pregnancy levels of placental corticotropin-releasing hormone, have been implicated in postpartum depression (Yim et al. 2009). Neuroreceptor downregulation following delivery may also contribute to the onset of postpartum depression (Maguire and Moody 2008).

Bipolar postpartum depression is often overlooked and mistaken for unipolar major depressive disorder (Sharma et al. 2009). Furthermore, women who have experienced a postpartum psychiatric episode are at heightened risk of developing bipolar disorder in the future (Munk-Olsen et al. 2012). Depressed mothers are more likely than nondepressed mothers to engage in negative parenting behaviors, and their children are at risk for behavioral and cognitive deficits from infancy to early childhood. Prompt and effective treatment of postpartum depression not only provides relief for new mothers but also reduces the likelihood of childhood behavior problems and patterns of insecure attachment.

A history of major depressive disorder increases the risk for postpartum major depressive disorder, and depression during pregnancy and a prior episode of postpartum further increases the likelihood of postpartum depression (O'Hara and Swain 1996; Llewellyn et al. 1997). Women who have had previous postpartum depression are at 50%-60% risk of another episode. Other risk factors for postpartum depression include stressful life events and lack of support from a partner or spouse or others (O'Hara and Swain 1996). Thyroid function should always be evaluated in postpartum women with depression or anxiety, because the postpartum period is a time of increased risk for thyroid dysfunction.

Postpartum depression is best treated comprehensively with individual and group psychotherapy, psychopharmacology, and psychoeducation. It is important to accurately diagnose postpartum depression as unipolar or bipolar, in order to provide safe, appropriate, and effective psychopharmacological treatment. Interpersonal (both individual and group) and cognitive-behavioral therapies are helpful in treating postpartum depression (Mulcahy et al. 2010). Standard antidepressants have been used successfully to treat unipolar postpartum depression. In cases of postpartum bipolar depression, standard bipolar treatment should include mood stabilizers and other augmenting agents required more acutely. Because antidepressants can precipitate mania in bipolar patients, caution should be exercised before treatment with an antidepressant. Decisions regarding medications should include consideration of whether the patient is breast-feeding (see section "Breast-Feeding and Psychotropic Medications" later in chapter). For new mothers with past histories of postpartum depression, studies of the effectiveness of prophylaxis with antidepressant medications, begun within 24-48 hours after delivery, have produced mixed results. Telephone-based peer support may be effective in preventing postpartum depression in women at risk for depression following delivery (Dennis et al. 2009). All women with a history of postpartum depression should be carefully monitored for signs of relapse throughout pregnancy and the postpartum period. Lay advocacy groups (e.g., Postpartum Support International) and Web-based education are available for primary care professionals, as well as for patients and their families (Wisner et al. 2008). Interpersonal difficulties between the patient and her partner are best addressed with conjoint therapy. Assistance with household duties and childcare provides the patient with opportunities to reduce sleep deprivation.

Note. ECT=electroconvulsive therapy.

The issue of whether or not to breastfeed should be discussed thoroughly, because nursing may alter the treatment modality or influence the choice of medication should pharmacotherapy be indicated. For patients whose depression is complicated by psychosis or suicidal thoughts, ECT is often the treatment of choice to hasten rapid improvement.

Postpartum Psychosis

The most serious postpartum illness, postpartum psychosis, occurs in 1-2 of every 1,000 births. Most cases of postpartum psychosis are thought to be a manifestation of bipolar disorder. The condition is characterized by mood lability, agitation, confusion, thought disorganization, hallucinations, and disturbed sleep. Women with postpartum psychosis are at risk for subsequent bipolar disorder. A family history of bipolar disorder also appears to heighten the risk for postpartum psychosis.

Because postpartum psychosis carries with it the risk of suicide, infant neglect, and infanticide, patients should be hospitalized. The initial evaluation includes a medical assessment to rule out organic etiologies such as postpartum thyroiditis, Sheehan's syndrome, pregnancy-related autoimmune disorders, HIV-related infection, and intoxication or withdrawal states. Acute pharmacological treatment includes a mood stabilizer, an antipsychotic, and a benzodiazepine as needed for agitation. Antidepressants should be administered with great caution, because they may provoke mania. Maintenance treatment for the patient whose postpartum psychosis was preceded by chronic recurrent affective illness involves long-term treatment with a mood stabilizer. For patients without a psychiatric history other than a single episode of postpartum psychosis, medications are often tapered and discontinued by 1 year of treatment, although these women should be followed, because they have approximately a 60% risk of recurrent affective illness. It is prudent for patients with a history of psychosis limited solely to the postpartum period who subsequently become pregnant to be placed on a prophylactic mood stabilizer immediately after delivery. However, to reduce relapse risk during pregnancy and the postpartum period, women with bipolar disorder should be treated antenatally and postnatally with a mood stabilizer (probably lithium; see discussion of mood stabilizers in pregnancy in earlier section on bipolar disorder).

Breast-Feeding and Psychotropic Medications

Approximately one-half of new mothers breast-feed. Breast-feeding enhances mother-infant bonding and is an excellent source of nutrition for infants. For women who require pharmacological treatment for postpartum psychiatric disorders, the decision of whether to forgo breast-feeding or to proceed with medications can be difficult. Table 38-10 lists issues that should be discussed with postpartum women with psychiatric illness when deciding whether or not to breast-feed. Although no medication should be taken by a breast-feeding woman without careful assessment of risks and benefits for the nursing baby, it is also important to consider the possible harm to a mother that withholding a drug can cause.

Guidelines for using psychotropic medication in breast-feeding mothers include apprising the infant's pediatrician of the need to monitor the infant carefully for potential adverse effects. The infant's baseline behavior and sleep and feeding patterns should be assessed before the nursing mother uses the medication. Infant hepatic drug clearance rises from about one-third of the mother's weight-adjusted clearance at birth to 100% at age 6 months. Thus, exposure to drugs through breast milk may be riskier in a neonate than in an older infant. Neonatologists should be consulted before premature infants are exposed to psychotropic medications through breast milk. Medications should be prescribed at the lowest dosage that achieves remission of psychiatric symptoms. Short-acting rather than long-acting medications are preferable, and supplementation of breast milk with formula reduces the infant's exposure to the drug. Because the clinical significance of any exposure to the baby of even small (and undetectable) doses of psychotropic agents is unknown, the baby's clinical status should be continually monitored.

Summary points for use of the major psychotropic drug classes in breastfeeding are provided in Table 38-11.

Most medications, including TCAs, benzodiazepines, and antipsychotic agents, have been classified by the American Academy of Pediatrics as "drugs whose effect on nursing infants is unknown but may be of concern" (American Academy of Pediatrics Committee on Drugs 2001). Data on the use of SSRIs and TCAs have been increasingly reassuring (Burt et al. 2001). Because infants nursed by mothers taking SSRIs, particularly paroxetine and sertraline, typically receive low serum levels of medication exposure, routine monitoring of serum concentrations is not necessary. MAOIs are best avoided, because they may cause hypertension in the infant.

Lithium is contraindicated by the American Academy of Pediatrics Committee on Drugs (2001) because adverse effects, including cyanosis, poor muscle tone, and electrocardiogram changes, have been noted in infants exposed to lithium through nursing. A study of nursing women receiving lithium monotherapy found that lithium concentrations in infant serum contained about one-quarter the concentration of lithium in maternal serum (Viguera et al. 2007). Although no significant clinical or behavioral effects were noted in the breast-fed infants, exposed infants at least up to age 6 weeks should be carefully monitored clinically and their sera should be evaluated for lithium, thyroid-stimulating hormone, blood urea nitrogen, and creatinine levels. Thus, because of the potential for thyroid, electrolyte, and fluid volume perturbations in such infants, the use of lithium during lactation is generally not recommended. Valproate and carbamazepine are considered by the Committee on Drugs to be compatible with breast-feeding; however, there have been rare reports of hepatic dysfunction and one possible case of transient seizure-like activity in infants exposed to carbamazepine via breast milk. Even though valproate accumulates in breast milk to a lesser extent than does carbamazepine, it should be used with caution in breastfeeding mothers, because it has been associated with infant hepatotoxicity. Whereas lamotrigine clearance increases during pregnancy, the dosage of this agent is often increased to ensure mood stability in bipolar women. After delivery, over the course of 2-3 weeks, clearance rapidly returns to preconception levels. Lamotrigine milk-to-plasma ratios are highly variable. Although data from more than 50 babies exposed to lamotrigine have not revealed adverse effects in exposed nurslings, one case of an infant who experienced severe apnea has been reported (Nordmo et al. 2009).

The American Academy of Pediatrics suggests that occasional use of shortacting benzodiazepines is compatible with breast-feeding. A recent prospective study found that when mothers took a single benzodiazepine while breast-feeding, their infants did not show signs of central nervous system depression (Kelly et al. 2012). Infants breast-fed by mothers taking a benzodiazepine in addition to another psychotropic medication did tend to be more sedated. Nevertheless, it is prudent to monitor benzodiazepine-exposed infants for sedation or other possible side effects.

Perimenopause and Menopause

Perimenopausal Depression and Anxiety

Menopause refers to the cessation of ovulation and menstrual cycling and usually occurs between ages 44 and 55 years (average age, 51.4 years). Perimenopause (climacteric) describes the years before menopause when ovarian function begins to decline. Numerous studies support the increased risk for depression and anxiety in women during the menopausal transition (Soares et al. 2010). Although perimenopausal depression cannot be fully explained by vasomotor discomfort, the extent to which hot flushes and adverse life events contribute to negative mood during the menopausal transition remains unclear. Risk factors for perimenopausal depression include a history of depression (including postpartum and premenstrual), vasomotor symptoms, sleep difficulties, chronic health problems, loss of significant others, and psychosocial problems.

Treatment

Some studies have found that estrogen (e.g., transdermal 17(3-estradiol) produces mood-elevating effects in perimenopausal and surgically menopausal women, but not in postmenopausal women. At this time, estrogen alone is not accepted for long-term treatment of clinical depression. Whether estrogen may prime or augment standard antidepressants in perimenopausal depressed women is unclear.

For perimenopausal women with major depressive disorder, standard antidepressant treatment, often including psychotherapy, is considered as first-line treatment. For perimenopausal women with severe hot flushes or night sweats who report subclinical depression and lethargy, hormone therapy (HT) may relieve the psychological symptoms as the vasomotor symptoms become less distressing. As women experience vasomotor symptom relief (usually within 2 weeks of beginning hormone replacement), depressive symptoms also should improve. If, after resolution of vasomotor symptoms, depression persists or worsens, standard psychiatric treatment should be initiated. Psychosocial factors that may contribute to depressed mood also should be addressed, including caring for aging parents, new-onset health problems in the patient or her spouse, financial difficulties, and changes in sexuality of the patient or her partner.

Hormone Therapy

HT incurs both benefits and risks. In addition to relieving vasomotor symptoms, estrogen therapy protects against osteoporotic bony changes and urogenital atrophy. Although estrogen increases the risk of endometrial cancer, the addition of a progestin in women with an intact uterus negates this risk. The Women's Health Initiative, a large prospective, randomized, placebo-controlled study, evaluated the risks and benefits of hormone treatment on coronary events, stroke, pulmonary embolism, breast cancer, bone health, and cognition in 27,000 postmenopausal women. A recent review of randomized, placebo-controlled trials of menopausal hormone therapy, including the Women's Health Initiative, which has now accrued 11 years of follow-up data, found that overall, women taking estrogen and progesterone or estrogen alone had fewer fractures but more strokes, blood clots, gallbladder disease, and urinary incontinence. Estrogen plus progestin increased the risk for breast cancer and probable dementia, whereas estrogen alone did not appear to increase the risk for breast cancer (Nelson et al. 2012). Initial findings of an association between combination hormone therapy and heart disease are weaker than originally suggested. Although it had been suggested that women who initiated HT closer to menopause tended to have a reduced risk for coronary heart disease compared with those who began HT more distant from the time of their last menstrual period (Rossouw et al. 2007), more recent evidence suggests that estrogen plus progestin therapy does not reduce the risk for coronary heart disease during the first 3-6 years of use in women who began therapy close to menopause (Toh et al. 2010). Earlier data suggesting that combination hormone therapy protected against colon cancer were also found to be weaker.

The short-term use of estrogen for treatment of severe vasomotor symptoms and urogenital atrophy is acceptable for women up to age 59 or within 10 years of menopause (Stuenkel et al. 2012). In perimenopausal and postmenopausal women who are at high risk for osteoporosis, estrogen replacement may be appropriate. However, HT as a primary long-term treatment to prevent heart disease and cognitive decline in postmenopausal women is not justified. Local low-dose estrogen therapy is effective and preferred for treatment of vaginal dryness. More data are needed before short-term estrogen therapy can be considered a primary mode of treatment for depression in perimenopausal women.

Eating Disorders

For many women, the pursuit of a body size and shape that seems personally desirable leads beyond dieting to disturbed eating behaviors. Some undereat, lose weight, and develop anorexia nervosa. Others overeat, often in the context of failing weight loss attempts, and either purge their excess calories, ultimately developing bulimia nervosa, or retain them, ultimately developing binge-eating disorder. Despite the near ubiquity of dieting, anorexia nervosa and bulimia nervosa affect only l%-3% of young women. These low rates may reflect the stringency of current criteria, however, because subclinical eating disturbances affect up to 25% of college-age women. DSM-5 reduces the frequency criterion for binge behavior in both bulimia nervosa and binge-eating disorder, allowing more patients to qualify for those diagnoses. Most eating disorders begin between ages 10 and 20 years, and the age at onset is decreasing steadily (Preti et al. 2009; Rosen 2010). Most adolescents have sub-clinical eating disorder diagnoses in association with increased rates of mood and anxiety symptoms and substantial body image disturbances (Touchette et al. 2011). During adolescence, actual weight loss may be minimal because calorie restriction may appear as a slowed increase in height and weight. Abnormal eating behaviors are often not revealed despite fatigue, bloating, irregular menses, infertility, low mood, anxiety, and worry.

Course and Outcome

Eating disturbances resolve for most youngsters, but psychiatric comorbidity and impaired psychosocial functioning remain in almost half the subjects followed (Lewinsohn et al. 2000; Råstam et al. 2003). Community and clinical studies of adults with bulimia nervosa show improvement when subjects are followed for 5 or more years; in one study, up to 75% of patients had no eating disorder at 20-year follow-up (Keel et al. 2010). Shorter duration of illness and early improvement in negative affect predict good outcome, whereas comorbid substance abuse and familial obesity make progress more difficult to achieve. Adult anorexia is less responsive than bulimia nervosa; few patients fully recover, and persistent body image disturbances, disordered eating, and social isolation, along with psychiatric comorbidity, are common. Mortality is high, and the odds of completed suicide are more than 13 times the expected rate (Papadopoulos et al. 2009). The outcome is brighter for adolescent anorexia nervosa, although residual anxious and obsessive symptoms often remain.

Screening and Assessment

The SCOFF, a five-question screening tool for assessing eating disorders, has demonstrated good validity in student and primary care populations (Hill et al. 2010). The questionnaire poses five questions, which include whether the patient makes herself sick when uncomfortably full, feels as if she has lost control over how much she eats, has recently lost 14 or more pounds in a 3-month period, believes that she is fat despite others' comments to the contrary, and believes that food dominates her life. Each yes answer is given 1 point, with a score of 2 or greater indicating the likelihood of anorexia nervosa or bulimia nervosa. Once the need for further assessment is clarified, a variety of self-report and structured evaluation forms for interview use are available; keeping these tools handy in the office enables the psychiatrist to focus the intake as needed when eating issues arise (Bellace et al. 2012).

Medical complications from anorexia nervosa and bulimia nervosa include electrocardiographic abnormalities, hypotension, esophageal perforation, rectal prolapse, metabolic alkalosis, hypokalemia, amenorrhea, osteoporosis, erosion of dental enamel, parotid and sub-mandibular gland hypertrophy, and anemia. Physical examination and dental examination should be followed by laboratory tests (complete blood count, comprehensive metabolic panel, and amylase [a measure of bingeing, not purging status]). In bingeeating disorder, metabolic syndrome is seen in almost half of overweight or obese patients and suggests evaluation of lipids, blood pressure, insulin resistance, and inflammatory markers. In adolescents, because some starvation-related changes may become irreversible, growth retardation and low bone mineral density require monitoring and attention.

Women with recent or current eating disturbances have difficulty conceiving and often seek fertility treatment. Once pregnant, women with a recent past history of an active eating disorder are more likely to relapse and experience high rates of depression during pregnancy as well as in the postpartum period. For some, maternity brings freedom from fear of eating and represents an opportunity to alter fixed beliefs about shape and weight that, if reinforced with treatment, may promote recovery.

Patients should be hospitalized when weight loss persists despite intensive outpatient treatment when food is refused; when body mass index drops below 17.5; or when there is evidence of psychosis, suicidality, or profound denial of the seriousness of the illness and/or signs of medical instability.

Table 38-12 summarizes the epidemiology, similarities, differences, and treatments for anorexia nervosa, bulimia nervosa, and binge-eating disorder.

Note. CBT=cognitive-behavioral therapy; IPT=interpersonal psychotherapy.

Conclusion

When assessing and treating women with psychiatric disorders, it is important that clinicians recognize gender-specific issues related to diagnosis, course, and treatment. These gender-specific differences are undoubtedly due to a combination of biological, genetic, and psychosocial factors. Thus, psychopharmacological and psychotherapeutic treatment modalities should address the special and changing needs of women over the course of their lives.

Key Clinical Points

• Although women and men are at equal lifetime risk of developing a psychiatric disorder, there are gender-specific differences in prevalence, clinical course, and treatment of specific psychiatric illnesses.
• Women are at particular risk for mood disorders at times of reproductive transition.
• When diagnosed properly, premenstrual dysphoric disorder responds robustly to treatment with selective serotonin reuptake inhibitors.
• The overall mental health of an expectant mother is an important determinant of the health and well-being of both mother and fetus.
• Decisions regarding the use of psychiatric medications in pregnancy are best made after assessing whether it is riskier to both mother and fetus for the mother to have symptomatic psychiatric illness or to be treated with a medication to effectively treat that illness.
• Although the antenatal use of many commonly used antidepressants has been associated with an increased risk of some adverse effects in pregnancy, when risks are balanced against benefits for women with serious mental illness, these agents are often judged to be necessary for the health and well-being of the mother and her fetus.
• Up to 60% of women with bipolar disorder become unstable if their mood stabilizer is discontinued when they become pregnant.
• Women with bipolar disorder are at substantially increased risk for postpartum mood disorders, including postpartum depression and postpartum psychosis.
• Women are at increased risk for major depressive disorder as they move into and through perimenopause. That risk is particularly great for those with a past history of major depressive disorder.
• Treatment of women with psychiatric disorders requires a careful and comprehensive assessment of physiological, genetic, reproductive, medical, and psychosocial risks for current illness as well as relapse and recurrence potential. In light of this assessment, the mental health clinician should choose among varying treatment options to maximize the best possible outcome for the patients, their babies and children, and their families.

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Rossouw JE, Prentice RL, Manson JE, et al: Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297:1465-1477, 2007

Rubinow DR: Antidepressant treatment during pregnancy: between Scylla and Charybdis (editorial). Am J Psychiatry 163: 954-956, 2006

Sharma V, Pope CJ: Pregnancy and bipolar disorder: a systematic review. J Clin Psychiatry 73:1447-1455, 2012

Sharma V, Burt VK, Ritchi HL: Assessment and treatment of bipolar II postpartum depression: a review. J Affect Disord 125:18-26, 2009

Soares CN, Frey BN: Challenges and opportunities to manage depression during the menopausal transition and beyond. Psychiatr Clin North Am 33:296-308, 2010

Sørensen MJ, Gronborg TK, Christensen J, et al: Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol 5:449-459, 2013

Steiner M, Pearlstein T, Cohen LS, et al: Expert guidelines for the treatment of severe PMS, PMDD, and comorbidities: the role of SSRIs. J Womens Health (Larchmt) 15:57-69, 2006

Stuenkel CA, Gass MLS, Manson JE, et al: A decade after the Women's Health Initiative—the experts do agree. Fertil Steril 98:313-314, 2012

Suri R, Altshuler L, Hellemann G, et al: Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry 164:1206-1213, 2007

Suri R, Hellemann G, Stowe ZN, et al: A prospective, naturalistic, blinded study of early neurobehavioral outcomes for infants following prenatal antidepressant exposure. J Clin Psychiatry 72:102-107, 2011

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U.S.Food and Drug Administration: Selective serotonin reuptake inhibitor (SSRI) antidepressants: drug safety communication—use during pregnancy and potential risk of persistent pulmonary hypertension of the newborn. December 14, 2011. Available at: http://www.fda.gov/Safety/MedWatch/Safetylnformation/Safety-AlertsforHumanMedicalProducts/ucm283696.htm. Accessed August 2, 2013.

Van den Bergh BR, Mulder EJ, Mennes M, et al: Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review. Neuro-sci Biobehav Rev 29:237-258, 2005

Van den Bergh BR, Van Calster B, Smits T, et al: Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood. Neuropsychopharmacology 33:536-545, 2008

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Viguera AC, Newport DJ, Ritchie J, et al: Lithium in breast milk and nursing infants: clinical implications. Am J Psychiatry 164:342-345, 2007

Viguera AC, Tondo L, Koukopoulos AE, et al: Episodes of mood disorders in 2,252 pregnancies and postpartum periods. Am J Psychiatry 168:1179-1185, 2011

Weikum WM, Oberlander TF, Hensch TK, et al: Prenatal exposure to antidepressants and depressed maternal mood alter trajectory of infant speech perception. Proc Natl Acad Sci USA 109 (suppl 2):17221-17227, 2012

Wichman CL, Moore KM, Lang TR, et al: Congenital heart disease associated with selective serotonin reuptake inhibitor use during pregnancy. Mayo Clin Proc 84:23-27, 2009

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Wisner KL, Logsdon MC, Shanahan BR: Web-based education for postpartum depression: conceptual development and impact. Arch Womens Ment Health 11:377-385.2008

Wisner KL, Sit D KY, Hanusa BH, et al: Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry 166:557-566.2009

Yim IS, Glynn LM, Schechter CD, et al: Risk of postpartum depressive symptoms with elevated corticotrophin-releasing hormone in human pregnancy. Arch Gen Psychiatry 66:162-169, 2009

Yonkers KA, Holthausen GA, Poschman KP, et al: Symptom-onset treatment for women with premenstrual dysphoric disorder. J Clin Psychopharmacol 26:198-202, 2006

Suggested Readings

Cohen LS, Altshuler LL, Harlow BL, et al: Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 295:499-507, 2006

Cohen LS, Soares CN, Vitonis AF, et al: Risk for new onset of depression during the menopausal transition. Arch Gen Psychiatry 63:385-390, 2006

Rubinow DR: Antidepressant treatment during pregnancy: between Scylla and Charybdis (editorial). Am J Psychiatry 163: 954-956, 2006

Sharma V, Pope CJ: Pregnancy and bipolar disorder: a systematic review. J Clin Psychiatry 73:1447-1455, 2012

Soares CN, Frey BN: Challenges and opportunities to manage depression during the menopausal transition and beyond. Psychiatr Clin North Am 33:296-308, 2010

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. Gen Hosp Psychiatry 31:403-413, 2009

Online Resources

Massachusetts General Hospital Center for Women's Mental Health: www.womensmentalhealth.org. Web site of the Massachusetts General Hospital Reproductive Psychiatry Resource and Information Center. Provides information about psychiatric conditions in women, including premenstrual dysphoric disorder, postpartum disorders, and peri-menopausal mood changes.

MedEdPPD: www.MedEdPPD.org. A professional education, peer-reviewed Web site with the goals of furthering the education of primary care providers who treat women who have or are at risk for postpartum depression, and to provide information for women with postpartum depression and their friends and family members.

Motherisk: www.motherisk.org. Canadian organization that provides information on safety and risks of drugs in pregnancy and lactation, and about alcohol and other substance use in pregnancy.

National Eating Disorders Association: www.edap.org. Nonprofit organization dedicated to the prevention and treatment of eating disorders. Provides referrals to patients with eating disorders and those concerned with body image and weight issues.

North American Menopause Society: www.menopause.org. Nonprofit organization promoting women's health during midlife and beyond, with special focus on menopausal health.

Postpartum Support International: http://postpartum.net. International network of individuals and organizations whose purpose is to increase awareness among public and professionals about pregnancy- and postpartum-related psychiatric disorders. Provides referrals for group and individual therapy, and for psychiatrists to women with postpartum disorders.