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Bipolar Disorder in Women a
a
b
Laura J. Miller , Nafisa Y. Ghadiali , Elizabeth M. Larusso , Kelly J. c
d
Wahlen , Orit Avni-Barron , Leena Mittal
de
& Judy A. Greene
f
a
Department of Psychiatry, Loyola Stritch School of Medicine, Edward Hines Jr. VA Hospital, Hines, Illinois, USA b
Allina Mental Health, Abbott Northwestern Hospital, Minneapolis, Minnesota, USA c
Milwaukee County Behavioral Health Division, Milwaukee, Wisconsin, USA d
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
Click for updates
e
Department of Psychiatry, Brigham and Women's Hospital, Brookline, Massachusetts, USA f
Psychiatry Division, Women's Mental Health, Bellevue Hospital Center, New York, New York, USA Accepted author version posted online: 14 Oct 2014.Published online: 20 Dec 2014.
To cite this article: Laura J. Miller, Nafisa Y. Ghadiali, Elizabeth M. Larusso, Kelly J. Wahlen, Orit Avni-Barron, Leena Mittal & Judy A. Greene (2015) Bipolar Disorder in Women, Health Care for Women International, 36:4, 475-498, DOI: 10.1080/07399332.2014.962138 To link to this article: http://dx.doi.org/10.1080/07399332.2014.962138
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content.
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This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/termsand-conditions
Health Care for Women International, 36:475–498, 2015 Copyright © Taylor & Francis Group, LLC ISSN: 0739-9332 print / 1096-4665 online DOI: 10.1080/07399332.2014.962138
Bipolar Disorder in Women LAURA J. MILLER and NAFISA Y. GHADIALI Department of Psychiatry, Loyola Stritch School of Medicine, Edward Hines Jr. VA Hospital, Hines, Illinois, USA
ELIZABETH M. LARUSSO Downloaded by [Lakehead University] at 13:02 06 April 2015
Allina Mental Health, Abbott Northwestern Hospital, Minneapolis, Minnesota, USA
KELLY J. WAHLEN Milwaukee County Behavioral Health Division, Milwaukee, Wisconsin, USA
ORIT AVNI-BARRON Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
LEENA MITTAL Department of Psychiatry, Harvard Medical School, Boston; and Department of Psychiatry, Brigham and Women’s Hospital, Brookline, Massachusetts, USA
JUDY A. GREENE Psychiatry Division, Women’s Mental Health, Bellevue Hospital Center, New York, New York, USA
This article summarizes research pertinent to the clinical care of women with bipolar disorder. With bipolar disorder, female gender correlates with more depressive symptoms and different comorbidities. There is a high risk of symptom recurrence postpartum and possibly during perimenopause. Women with bipolar disorder have increased risk of sexually transmitted diseases, unplanned pregnancies, excessive weight gain, metabolic syndrome, and cardiovascular disease. Mood stabilizing medications, specific psychotherapies, and lifestyle changes can stabilize mood and improve functioning. Pharmacologic considerations include understanding interactions between mood stabilizing medications and contraceptive agents and risks and benefits of mood stabilizing medication during pregnancy and lactation. Received 7 January 2014; accepted 2 September 2014. Address correspondence to Laura J. Miller, Department of Psychiatry, Loyola Stritch School of Medicine, Edward Hines Jr. VA Hospital, 5000 S. 5th Avenue, Building 228, Room 1016, Hines IL, 60141, USA. E-mail: [email protected] 475
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Bipolar disorder is a leading cause of disability worldwide (Merikangas et al., 2011). Bipolar disorder type I (BD-I) is diagnosed in patients who have had at least one manic episode, consisting of euphoric. irritable, or both moods for at least a week along with at least three other manic symptoms (grandiosity, reduced need for sleep, increased talking, racing thoughts, distractibility, increased goal-directed activity, and excessive highrisk pleasurable activities) resulting in marked functional impairment. Bipolar disorder type II (BD-II) is diagnosed in patients who have had episodes of major depression and of hypomania, defined as at least four days of manic symptoms with resultant functional impairment (American Psychiatric Association, 2013). Lifetime prevalence for bipolar disorders is approximately 4.4% in the United States (Merikangas et al., 2007); worldwide lifetime prevalence is about 0.6% for BD-I and about 0.4% for BD-II (Merikangas et al., 2011). In this review, we summarize clinically relevant research about aspects of bipolar disorder pertinent to women, including gender differences in clinical presentation, reproductive cycle influences, sexuality, contraception, and medical comorbidities. We review considerations for pharmacotherapy, psychotherapy and other interventions with particular relevance for women. We identified relevant studies upon which to base our review by electronically searching the English-language literature via the following databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, OvidMD, PsycINFO, and PubMed. We prioritized inclusion of findings from randomized, double-blind, prospective controlled studies and metaanalyses with defined quality criteria regarding study design. When such studies were not available regarding a clinically relevant topic, we included findings from retrospective controlled studies and nonrandomized prospective controlled studies. We included pilot studies and case series when they represented promising new approaches to understanding and treating bipolar disorder in women, when they shed light on potentially clinically important risks, or both possibilities.
GENDER DIFFERENCES In most studies, the prevalence, age of onset, and severity of bipolar disorder are comparable in men and women (Hendrick, Altshuler, Gitlin, Delrahim, & Hammen, 2000; Smith, Nicholl, & Cullen, 2013), but women have more depressive episodes (Altshuler, Kupka, & Hellemann, 2010; Nivoli, Pacchiarotti, & Rosa, 2011). Mixed episodes, in which both manic and depressive symptoms are present, have been found to be more common in women than men (Benazzi, 2003; Grant et al., 2005; Kessing, 2008; Suppes et al., 2005). The relative prominence of depressive symptoms in women may contribute to delayed diagnosis; for example, Viguera, Baldessarini, and Tondo (2001) found that women with bipolar disorder were misdiagnosed with unipolar
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depression for 1.9 years longer than men, and started maintenance treatment 5.5 years later on average. During bipolar depressive episodes, more women than men report weight and appetite changes, hypersomnia, and difficulty maintaining nighttime sleep (Benazzi, 2003; Kawa, Carter, & Joyce, 2005). During manic episodes, fewer women than men report problem behaviors, hyperactivity, or heightened sexual interest (Bhattacharya et al., 2011; Kawa et al., 2005; Young et al., 2007). Women are more likely than men to have more frequent depressive episodes in fall and winter (Baldassano et al., 2005). Psychiatric comorbidities are also influenced by gender, with more women than men concomitantly diagnosed with posttraumatic stress disorder, eating disorders, and personality disorders (Baldassano et al., 2005; Kawa et al., 2005; McElroy et al., 2010; Nivoli et al., 2011; Suominen et al., 2009).
REPRODUCTIVE CYCLE INFLUENCES Menstrual Cycle To date, most researchers have found no connection between bipolar mood symptoms and menstrual cycle phases (Karadag et al., 2004; Leibenluft, Ashman, Feldman-Naim, & Yonkers, 1999; Rasgon, Glenn, Elman, & Whybrow, 2003; Shivakumar et al., 2008; Sit, Seltman, & Wisner, 2011). Brockington (2011) has reported cases of women with bipolar disorder who have menstrual cycle-linked symptom exacerbations. In some instances, these include psychotic features that consistently recur during a particular menstrual cycle phase. Prospective daily charting can be used to distinguish premenstrual symptom exacerbation from other types of rapid cycling bipolar disorder. Menstrual irregularities have been reported at higher rates among women with bipolar disorder compared with those with unipolar depression or no psychiatric disorder, often preceding treatment (Joffe et al., 2006b). Valproate has been associated with new onset menstrual irregularity (Joffe et al., 2006a; Rasgon et al., 2005). Menstrual phase can affect mood stabilizer pharmacokinetics. In some but not most women, serum lithium levels are lower in the luteal phase than in the follicular phase (Chamberlain, Hahn, Casson, & Reid, 1990).
Pregnancy There is no clear evidence that pregnancy affects risk of bipolar mood episodes. Evidence that pregnancy is protective is scant, consisting of case reports (Sharma & Persad, 1995) and a small (N = 23) retrospective study with a nonrepresentative clinical sample (Grof, Robbins, & Alda, 2000). What is clear is that pregnant women with bipolar disorder who discontinue mood stabilizing medications have high recurrence rates, as well as
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shorter time to recurrence and considerably more time ill compared with pregnant women who maintain medication (Viguera et al., 2007). Recurrence risk is especially high for women who discontinue mood stabilizing medications abruptly rather than gradually, and for women who take antidepressants. This does not necessarily mean that pregnancy per se increases risk. In a retrospective study (Viguera et al., 2000), recurrence rates were similar for women with bipolar disorder in the 40 weeks after discontinuing mood stabilizing medication, whether pregnant or not. Pregnancy, however, is a time when women are especially likely to consider discontinuing medication. Fetal risks associated with untreated bipolar disorder may include premature delivery and low birth weight (Lee & Lin, 2010). Additional risks of untreated mood episodes during pregnancy are high-risk impulsive behaviors, poor self-care, addictive substance use, and suicide attempts.
Postpartum The risk of recurrence of a bipolar mood episode is significantly higher postpartum than during pregnancy or in non-perinatal periods (Di Florio et al., 2013; Viguera et al., 2011). Approximately 49%–67% of women with bipolar disorder who give birth experience postpartum mood disturbance (Freeman et al., 2002). Women with prior postpartum episodes are at especially high risk for subsequent postpartum episodes (Blehar et al., 1998; Freeman et al., 2002). Symptoms usually begin within the first 4 weeks after delivery (Di Florio et al., 2013). In addition to abrupt hormonal flux, other posited influences on postpartum relapse include sleep deprivation, circadian rhythm disruption, new stressors, and social role transitions. For women with new-onset depressive episodes postpartum, distinguishing bipolar from unipolar depression can be challenging. In one large study (Azorin et al., 2012), when first lifetime depressive episodes were postpartum, they included increased rates of hypomanic and psychotic symptoms, with higher rates of subsequent bipolar diagnosis. In another study, depression onset within 2 weeks after delivery was associated with subsequent development of bipolar disorder (Munk-Olsen, Laursen, MeltzerBrody, Mortensen, & Jones, 2012). In Table 1, we summarize clinical indicators raising a higher suspicion of bipolar disorder for women with postpartum depressive episodes. Another diagnostic dilemma is distinguishing postpartum hypomanic symptoms from normal happiness. Postpartum hypomanic symptoms are estimated to occur in 10%–18% of women giving birth (Glover, Liddle, Taylor, Adams, & Sandler, 1994; Lane et al., 1997; Smith et al., 2009). By contrast with normal happiness, hypomanic symptoms may include racing thoughts, reduced need for sleep, and excessive, rapid talking.
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TABLE 1 Clinical Indicators of Possible Bipolar Disorder for Women With New-Onset Postpartum Depression Item
Increased likelihood of bipolar disorder
Past hypomanic symptoms, not necessarily recognized as problematic or part of an illness Family history Biological relatives with bipolar disorder Screening scores Positive score on the Mood Disorders Questionnaire Symptom onset Within first 2–4 weeks postpartum Symptom presentation Presence of: • Psychotic symptoms • Mixed features (e.g., agitation, irritability, hypomanic symptoms mixed with depressive symptoms) Treatment response Poor response to antidepressant medication, including heightened mood instability
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History
Sources: Azorin et al., 2012; Munk-Olsen et al., 2012; Sharma, Khan, & Sharma, 2008.
Women with bipolar disorder are at high risk of postpartum psychosis. Postpartum psychosis is rare in the general population, affecting one to two childbearing women per thousand. By contrast, about 26% of childbearing women with bipolar disorder have postpartum psychosis, usually within the first 3e weeks (Jones & Craddock, 2001). Symptoms may include hallucinations, delusions, mood lability, impaired insight and judgment, confusion, memory impairment, and altered sensorium resembling delirium. Symptom severity may wax and wane substantially more than during nonpostpartum psychotic mood episodes (Wisner, Peindl, & Hanusa, 1994). Temporary symptom waning can be confused with recovery, and it can lead to missed diagnoses when symptoms are less apparent during examination. Hallucinations and delusions may be related to the infant and, in rare cases, may contribute to a risk of harm to the infant (Spinelli, 2009). Inquiring directly and no-judgmentally about thoughts of suicide, harming the baby, or both can improve detection and prompt treatment of these psychiatric emergencies. In women with bipolar disorder, the risk of postpartum mood episodes can be reduced by stabilizing circadian and social rhythms, and initiating or maintaining mood stabilizing medication (Bergink et al., 2012). Preventing excessive sleep disruption is particularly important. This sometimes necessitates modifying breastfeeding if it is substantially disrupting sleep.
Perimenopause Studies of the effect of the menopausal transition on the course of bipolar disorder are sparse, but their findings are consistent with possible heightened risk of depressive symptoms. In a study of 164 patients with bipolar disorder,
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women ages 45–55 had more study visits with depressive symptoms and fewer euthymic study visits than the combined pool of similarly aged men, younger women, and younger men (ages 30–40; Marsh, Ketter, & Rasgon, 2009). In another study of 27 perimenopausal women with bipolar disorder, participants experienced increased frequency of depressive episodes and total mood episodes during in-clinic perimenopausal years compared with self-report of years prior (Marsh, Templeton, Ketter, & Rasgon, 2008). There is some evidence that estrogen may alleviate depressive symptoms, although not major depressive episodes, in perimenopausal women with unipolar depression. It is not known whether this is the case for bipolar depressive symptoms. Since there have been cases of estrogen-induced mania (Young, Moline, & Kleyman, 1997), it is advisable to mention this possible side effect and to monitor for manic symptoms. Perimenopausal night sweats and urinary frequency can disrupt sleep, which can destabilize mood. Identifying and managing these sleep disruptors may reduce risk of perimenopausal symptom exacerbation.
GENDER-INFLUENCED MEDICAL COMORBIDITIES Adiposity and Metabolic Dysfunction Women who are overweight or obese have a higher prevalence of bipolar disorder compared with women of normal weight (Barry, Pietrzak, & Petry, 2008). More than half of patients with bipolar disorder are overweight or obese, and higher body mass index (BMI) has been associated with greater depressive symptom severity and poorer treatment outcomes (Kemp et al., 2010). In a sample of people with bipolar disorder, obesity was correlated with female sex (Goldstein et al., 2011). There are likely multidirectional causal links between metabolic dysfunction, increased weight, and bipolar disorder apart from medication effects. Soreca, Frank, and Kupfer (2009) posit that there are common underlying vulnerabilities to emotion dysregulation and binge eating. Depressed states, more common in women than in men with bipolar disorder, may reduce energy expenditure.
Cardiovascular Disease Bipolar disorder has been associated with an approximately doubled risk of mortality from cardiovascular disease (CVD) compared with the general population (Westman et al., 2013). Risk factors for CVD that are elevated in people with bipolar disorder include hypertension, hyperlipidemia, and impaired endothelial function (Goldstein, Fagiolini, Houck, & Kupfer, 2009; Rybakowski, Wykretowicz, Heymann-Szlachcinska, & Wysocki, 2006).
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CVD may also be influenced by common comorbidities including cigarette smoking, heavy alcohol use, obesity, and insulin resistance, as well as the increased systemic inflammation seen during acute mood episodes. Among these risk factors, rates of abdominal obesity are significantly higher in women than in men with bipolar disorder (Gomes et al., 2013).
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Sexually Transmitted Diseases Impulsivity, hypersexuality, impaired judgment, and comorbid substance use disorders sometimes accompanying bipolar disorder place women at risk for ¨ sexually transmitted diseases (Ozcan, Boyacio˘glu, Enginkaya, Dinc¸, & Bilgin, 2014). Among patients with bipolar disorder and substance use disorders, over 75% reported high rates of sexual risk behaviors, with women more likely than men to report sex trading.
PSYCHOPHARMACOLOGIC CONSIDERATIONS FOR WOMEN WITH BIPOLAR DISORDER Agents approved by the Food and Drug Administration for the treatment of bipolar disorder, mania, or both include lithium, the anticonvulsant agents carbamazepine, lamotrigine and valproate, and the second-generation antipsychotic (SGA) agents aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. Of note given the relatively high prevalence of depressive episodes in women with bipolar disorder, mood stabilizers are generally more effective in treating and preventing mania than depression. Among mood stabilizing agents, lamotrigine appears to be relatively effective for treating and preventing bipolar depressive episodes (Goodwin et al., 2004). In the absence of mood stabilizing agents, antidepressants may precipitate mania (Valenti et al., 2012).
Mood Stabilizer Efficacy and Side Effects In general, women and men respond equally well to pharmacotherapy for bipolar disorder. Women, however, may respond to somewhat lower serum concentrations of lithium than men (Viguera, Baldessarini, & Tondo, 2001). Side effect considerations may be affected by gender. Among patients with bipolar disorder, women are more likely than men to fear weight gain and to identify it as the most worrisome medication side effect (Kriegshauser et al., 2010). Risperidone often causes hyperprolactinemia, sometimes resulting in galactorrhea, gynecomastia, menstrual abnormalities, sexual dysfunction, or all of these. Long-term prolactin elevation can reduce bone density (Meaney et al., 2004).
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Mood Stabilizers, Fertility, and Contraception Hyperprolactinemia from risperidone occasionally reduces fertility (Smith, Wheeler, Murray, & O’Keane, 2002). Valproate can predispose women to features of polycystic ovary syndrome (PCOS), including reduced ovulation and irregular menses (Hu et al., 2011). In addition, women with bipolar disorder have a higher prevalence of PCOS independently of the effects of valproate (Jiang, Kenna, & Rasgon, 2009). Women with bipolar disorder may be at high risk of unintended pregnancy. In a survey of 136 Brazilian women of childbearing age with bipolar disorder, 41% of study participants reported not using any contraception (Magalh˜aes, Kapczinski, & Kauer-Sant’Anna, 2009). There are significant drug–drug interactions between mood stabilizers and hormonal contraceptives. The enzyme-inducing mood stabilizers carbamazepine and oxcarbazepine increase clearance of combined oral contraceptive (COC) pills and transdermal patches, progestogen-only pills, and progestogen implants. By a different mechanism, lamotrigine may also reduce COC efficacy, although this is less well established (Sidhu, Job, Singh, & Philipson, 2006). Although some providers attempt to compensate by offlabel prescribing of higher-dose contraceptives, there is no confirmed dose range that assures adequate contraception. Alternate birth control methods include depot medroxyprogesterone acetate injections, copper intrauterine devices, and levonorgestrel-releasing intrauterine systems. Contraceptive agents may alter levels of mood stabilizers. Lamotrigine and valproate clearance increases substantially with use of estrogen-based contraceptives, such that plasma levels are considerably lower during the active phase of a contraceptive cycle than they are during the placebo phase (Herzog et al., 2009; Sidhu, Job, Singh, & Philipson, 2006). Women requiring these medications can consider nonestrogenic, including progestogen-only, contraception. Other factors influencing optimal contraceptive methods include sexual behavior patterns and ability to adhere to medication regimens. Women whose symptoms interfere with consistent daily pill use or preplanning for sexual encounters may benefit from longer-acting alternatives, particularly intrauterine devices (IUDs). In a study of 849 women with bipolar disorder using four types of contraception, women using IUDs were most likely to continue the method for at least 12 months (Berenson, Asem, Tan, & Wilkinson, 2011).
Mood Stabilizers, Pregnancy, and Breastfeeding Navigating pregnancy with bipolar disorder can be challenging, since both untreated symptoms and treatments pose risks. In most cases, risks of untreated symptoms outweigh risks of a carefully chosen medication regimen and appropriate monitoring. In Table 2, we summarize available data from
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• Right-sided cardiac defects • (0.05%–0.1%) • • Fetal nephrogenic diabetes insipidus (presenting as polyhydramnios, uterine enlargement, maternal shortness of breath) • Prematurity • Transient hypothyroidism • “Floppy baby” syndrome
Lithium
• •
• Pregnancy lowers serum level
• • • Neural tube defects (0.5%–1%) • • Possible increased bleeding risk due to • deficiency of Vitamin K-dependent clotting factors
• No systematic data
Pregnancy
Lamotrigine
Carbamazepine
Aripiprazole
Medication
Peripartum considerations
• Use in pregnancy based on risk/benefit analysis • Folate supplementation before and during pregnancy to reduce risk of neural tube defects • Ultrasound at 16–18 weeks gestation for exposure during period of neural tube formation (14–35 days after conception) • Vitamin K supplementation to newborn per pediatric recommendations 3.1%–21.1% of mother’s dose • Dose adjustment often needed during Increased platelet counts; apneic pregnancy due to increased clearance, with return to preconception levels episode, rash postpartum • Need to distinguish benign infant rash from Stevens-Johnson syndrome 0–30% of mother’s dose • Avoid period of cardiac formation Cyanosis, restlessness, muscle twitches, (days 18–55 after conception) when possible lethargy, hypothermia • Ultrasound, fetal echocardiography at 16–18 weeks gestation with early exposure • Monitor for polyhydramnios • Consider divided doses near term to reduce toxic peaks to newborn • Consider halving the dose at labor onset to reduce risk of maternal and neonatal toxicity • Risk of toxicity in breastfeeding babies increases with fever, dehydration (Continued on next page)
Health Care for Women International Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uhcw20
Bipolar Disorder in Women a
a
b
Laura J. Miller , Nafisa Y. Ghadiali , Elizabeth M. Larusso , Kelly J. c
d
Wahlen , Orit Avni-Barron , Leena Mittal
de
& Judy A. Greene
f
a
Department of Psychiatry, Loyola Stritch School of Medicine, Edward Hines Jr. VA Hospital, Hines, Illinois, USA b
Allina Mental Health, Abbott Northwestern Hospital, Minneapolis, Minnesota, USA c
Milwaukee County Behavioral Health Division, Milwaukee, Wisconsin, USA d
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
Click for updates
e
Department of Psychiatry, Brigham and Women's Hospital, Brookline, Massachusetts, USA f
Psychiatry Division, Women's Mental Health, Bellevue Hospital Center, New York, New York, USA Accepted author version posted online: 14 Oct 2014.Published online: 20 Dec 2014.
To cite this article: Laura J. Miller, Nafisa Y. Ghadiali, Elizabeth M. Larusso, Kelly J. Wahlen, Orit Avni-Barron, Leena Mittal & Judy A. Greene (2015) Bipolar Disorder in Women, Health Care for Women International, 36:4, 475-498, DOI: 10.1080/07399332.2014.962138 To link to this article: http://dx.doi.org/10.1080/07399332.2014.962138
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content.
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This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/termsand-conditions
Health Care for Women International, 36:475–498, 2015 Copyright © Taylor & Francis Group, LLC ISSN: 0739-9332 print / 1096-4665 online DOI: 10.1080/07399332.2014.962138
Bipolar Disorder in Women LAURA J. MILLER and NAFISA Y. GHADIALI Department of Psychiatry, Loyola Stritch School of Medicine, Edward Hines Jr. VA Hospital, Hines, Illinois, USA
ELIZABETH M. LARUSSO Downloaded by [Lakehead University] at 13:02 06 April 2015
Allina Mental Health, Abbott Northwestern Hospital, Minneapolis, Minnesota, USA
KELLY J. WAHLEN Milwaukee County Behavioral Health Division, Milwaukee, Wisconsin, USA
ORIT AVNI-BARRON Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA
LEENA MITTAL Department of Psychiatry, Harvard Medical School, Boston; and Department of Psychiatry, Brigham and Women’s Hospital, Brookline, Massachusetts, USA
JUDY A. GREENE Psychiatry Division, Women’s Mental Health, Bellevue Hospital Center, New York, New York, USA
This article summarizes research pertinent to the clinical care of women with bipolar disorder. With bipolar disorder, female gender correlates with more depressive symptoms and different comorbidities. There is a high risk of symptom recurrence postpartum and possibly during perimenopause. Women with bipolar disorder have increased risk of sexually transmitted diseases, unplanned pregnancies, excessive weight gain, metabolic syndrome, and cardiovascular disease. Mood stabilizing medications, specific psychotherapies, and lifestyle changes can stabilize mood and improve functioning. Pharmacologic considerations include understanding interactions between mood stabilizing medications and contraceptive agents and risks and benefits of mood stabilizing medication during pregnancy and lactation. Received 7 January 2014; accepted 2 September 2014. Address correspondence to Laura J. Miller, Department of Psychiatry, Loyola Stritch School of Medicine, Edward Hines Jr. VA Hospital, 5000 S. 5th Avenue, Building 228, Room 1016, Hines IL, 60141, USA. E-mail: [email protected] 475
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Bipolar disorder is a leading cause of disability worldwide (Merikangas et al., 2011). Bipolar disorder type I (BD-I) is diagnosed in patients who have had at least one manic episode, consisting of euphoric. irritable, or both moods for at least a week along with at least three other manic symptoms (grandiosity, reduced need for sleep, increased talking, racing thoughts, distractibility, increased goal-directed activity, and excessive highrisk pleasurable activities) resulting in marked functional impairment. Bipolar disorder type II (BD-II) is diagnosed in patients who have had episodes of major depression and of hypomania, defined as at least four days of manic symptoms with resultant functional impairment (American Psychiatric Association, 2013). Lifetime prevalence for bipolar disorders is approximately 4.4% in the United States (Merikangas et al., 2007); worldwide lifetime prevalence is about 0.6% for BD-I and about 0.4% for BD-II (Merikangas et al., 2011). In this review, we summarize clinically relevant research about aspects of bipolar disorder pertinent to women, including gender differences in clinical presentation, reproductive cycle influences, sexuality, contraception, and medical comorbidities. We review considerations for pharmacotherapy, psychotherapy and other interventions with particular relevance for women. We identified relevant studies upon which to base our review by electronically searching the English-language literature via the following databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, OvidMD, PsycINFO, and PubMed. We prioritized inclusion of findings from randomized, double-blind, prospective controlled studies and metaanalyses with defined quality criteria regarding study design. When such studies were not available regarding a clinically relevant topic, we included findings from retrospective controlled studies and nonrandomized prospective controlled studies. We included pilot studies and case series when they represented promising new approaches to understanding and treating bipolar disorder in women, when they shed light on potentially clinically important risks, or both possibilities.
GENDER DIFFERENCES In most studies, the prevalence, age of onset, and severity of bipolar disorder are comparable in men and women (Hendrick, Altshuler, Gitlin, Delrahim, & Hammen, 2000; Smith, Nicholl, & Cullen, 2013), but women have more depressive episodes (Altshuler, Kupka, & Hellemann, 2010; Nivoli, Pacchiarotti, & Rosa, 2011). Mixed episodes, in which both manic and depressive symptoms are present, have been found to be more common in women than men (Benazzi, 2003; Grant et al., 2005; Kessing, 2008; Suppes et al., 2005). The relative prominence of depressive symptoms in women may contribute to delayed diagnosis; for example, Viguera, Baldessarini, and Tondo (2001) found that women with bipolar disorder were misdiagnosed with unipolar
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depression for 1.9 years longer than men, and started maintenance treatment 5.5 years later on average. During bipolar depressive episodes, more women than men report weight and appetite changes, hypersomnia, and difficulty maintaining nighttime sleep (Benazzi, 2003; Kawa, Carter, & Joyce, 2005). During manic episodes, fewer women than men report problem behaviors, hyperactivity, or heightened sexual interest (Bhattacharya et al., 2011; Kawa et al., 2005; Young et al., 2007). Women are more likely than men to have more frequent depressive episodes in fall and winter (Baldassano et al., 2005). Psychiatric comorbidities are also influenced by gender, with more women than men concomitantly diagnosed with posttraumatic stress disorder, eating disorders, and personality disorders (Baldassano et al., 2005; Kawa et al., 2005; McElroy et al., 2010; Nivoli et al., 2011; Suominen et al., 2009).
REPRODUCTIVE CYCLE INFLUENCES Menstrual Cycle To date, most researchers have found no connection between bipolar mood symptoms and menstrual cycle phases (Karadag et al., 2004; Leibenluft, Ashman, Feldman-Naim, & Yonkers, 1999; Rasgon, Glenn, Elman, & Whybrow, 2003; Shivakumar et al., 2008; Sit, Seltman, & Wisner, 2011). Brockington (2011) has reported cases of women with bipolar disorder who have menstrual cycle-linked symptom exacerbations. In some instances, these include psychotic features that consistently recur during a particular menstrual cycle phase. Prospective daily charting can be used to distinguish premenstrual symptom exacerbation from other types of rapid cycling bipolar disorder. Menstrual irregularities have been reported at higher rates among women with bipolar disorder compared with those with unipolar depression or no psychiatric disorder, often preceding treatment (Joffe et al., 2006b). Valproate has been associated with new onset menstrual irregularity (Joffe et al., 2006a; Rasgon et al., 2005). Menstrual phase can affect mood stabilizer pharmacokinetics. In some but not most women, serum lithium levels are lower in the luteal phase than in the follicular phase (Chamberlain, Hahn, Casson, & Reid, 1990).
Pregnancy There is no clear evidence that pregnancy affects risk of bipolar mood episodes. Evidence that pregnancy is protective is scant, consisting of case reports (Sharma & Persad, 1995) and a small (N = 23) retrospective study with a nonrepresentative clinical sample (Grof, Robbins, & Alda, 2000). What is clear is that pregnant women with bipolar disorder who discontinue mood stabilizing medications have high recurrence rates, as well as
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shorter time to recurrence and considerably more time ill compared with pregnant women who maintain medication (Viguera et al., 2007). Recurrence risk is especially high for women who discontinue mood stabilizing medications abruptly rather than gradually, and for women who take antidepressants. This does not necessarily mean that pregnancy per se increases risk. In a retrospective study (Viguera et al., 2000), recurrence rates were similar for women with bipolar disorder in the 40 weeks after discontinuing mood stabilizing medication, whether pregnant or not. Pregnancy, however, is a time when women are especially likely to consider discontinuing medication. Fetal risks associated with untreated bipolar disorder may include premature delivery and low birth weight (Lee & Lin, 2010). Additional risks of untreated mood episodes during pregnancy are high-risk impulsive behaviors, poor self-care, addictive substance use, and suicide attempts.
Postpartum The risk of recurrence of a bipolar mood episode is significantly higher postpartum than during pregnancy or in non-perinatal periods (Di Florio et al., 2013; Viguera et al., 2011). Approximately 49%–67% of women with bipolar disorder who give birth experience postpartum mood disturbance (Freeman et al., 2002). Women with prior postpartum episodes are at especially high risk for subsequent postpartum episodes (Blehar et al., 1998; Freeman et al., 2002). Symptoms usually begin within the first 4 weeks after delivery (Di Florio et al., 2013). In addition to abrupt hormonal flux, other posited influences on postpartum relapse include sleep deprivation, circadian rhythm disruption, new stressors, and social role transitions. For women with new-onset depressive episodes postpartum, distinguishing bipolar from unipolar depression can be challenging. In one large study (Azorin et al., 2012), when first lifetime depressive episodes were postpartum, they included increased rates of hypomanic and psychotic symptoms, with higher rates of subsequent bipolar diagnosis. In another study, depression onset within 2 weeks after delivery was associated with subsequent development of bipolar disorder (Munk-Olsen, Laursen, MeltzerBrody, Mortensen, & Jones, 2012). In Table 1, we summarize clinical indicators raising a higher suspicion of bipolar disorder for women with postpartum depressive episodes. Another diagnostic dilemma is distinguishing postpartum hypomanic symptoms from normal happiness. Postpartum hypomanic symptoms are estimated to occur in 10%–18% of women giving birth (Glover, Liddle, Taylor, Adams, & Sandler, 1994; Lane et al., 1997; Smith et al., 2009). By contrast with normal happiness, hypomanic symptoms may include racing thoughts, reduced need for sleep, and excessive, rapid talking.
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TABLE 1 Clinical Indicators of Possible Bipolar Disorder for Women With New-Onset Postpartum Depression Item
Increased likelihood of bipolar disorder
Past hypomanic symptoms, not necessarily recognized as problematic or part of an illness Family history Biological relatives with bipolar disorder Screening scores Positive score on the Mood Disorders Questionnaire Symptom onset Within first 2–4 weeks postpartum Symptom presentation Presence of: • Psychotic symptoms • Mixed features (e.g., agitation, irritability, hypomanic symptoms mixed with depressive symptoms) Treatment response Poor response to antidepressant medication, including heightened mood instability
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History
Sources: Azorin et al., 2012; Munk-Olsen et al., 2012; Sharma, Khan, & Sharma, 2008.
Women with bipolar disorder are at high risk of postpartum psychosis. Postpartum psychosis is rare in the general population, affecting one to two childbearing women per thousand. By contrast, about 26% of childbearing women with bipolar disorder have postpartum psychosis, usually within the first 3e weeks (Jones & Craddock, 2001). Symptoms may include hallucinations, delusions, mood lability, impaired insight and judgment, confusion, memory impairment, and altered sensorium resembling delirium. Symptom severity may wax and wane substantially more than during nonpostpartum psychotic mood episodes (Wisner, Peindl, & Hanusa, 1994). Temporary symptom waning can be confused with recovery, and it can lead to missed diagnoses when symptoms are less apparent during examination. Hallucinations and delusions may be related to the infant and, in rare cases, may contribute to a risk of harm to the infant (Spinelli, 2009). Inquiring directly and no-judgmentally about thoughts of suicide, harming the baby, or both can improve detection and prompt treatment of these psychiatric emergencies. In women with bipolar disorder, the risk of postpartum mood episodes can be reduced by stabilizing circadian and social rhythms, and initiating or maintaining mood stabilizing medication (Bergink et al., 2012). Preventing excessive sleep disruption is particularly important. This sometimes necessitates modifying breastfeeding if it is substantially disrupting sleep.
Perimenopause Studies of the effect of the menopausal transition on the course of bipolar disorder are sparse, but their findings are consistent with possible heightened risk of depressive symptoms. In a study of 164 patients with bipolar disorder,
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women ages 45–55 had more study visits with depressive symptoms and fewer euthymic study visits than the combined pool of similarly aged men, younger women, and younger men (ages 30–40; Marsh, Ketter, & Rasgon, 2009). In another study of 27 perimenopausal women with bipolar disorder, participants experienced increased frequency of depressive episodes and total mood episodes during in-clinic perimenopausal years compared with self-report of years prior (Marsh, Templeton, Ketter, & Rasgon, 2008). There is some evidence that estrogen may alleviate depressive symptoms, although not major depressive episodes, in perimenopausal women with unipolar depression. It is not known whether this is the case for bipolar depressive symptoms. Since there have been cases of estrogen-induced mania (Young, Moline, & Kleyman, 1997), it is advisable to mention this possible side effect and to monitor for manic symptoms. Perimenopausal night sweats and urinary frequency can disrupt sleep, which can destabilize mood. Identifying and managing these sleep disruptors may reduce risk of perimenopausal symptom exacerbation.
GENDER-INFLUENCED MEDICAL COMORBIDITIES Adiposity and Metabolic Dysfunction Women who are overweight or obese have a higher prevalence of bipolar disorder compared with women of normal weight (Barry, Pietrzak, & Petry, 2008). More than half of patients with bipolar disorder are overweight or obese, and higher body mass index (BMI) has been associated with greater depressive symptom severity and poorer treatment outcomes (Kemp et al., 2010). In a sample of people with bipolar disorder, obesity was correlated with female sex (Goldstein et al., 2011). There are likely multidirectional causal links between metabolic dysfunction, increased weight, and bipolar disorder apart from medication effects. Soreca, Frank, and Kupfer (2009) posit that there are common underlying vulnerabilities to emotion dysregulation and binge eating. Depressed states, more common in women than in men with bipolar disorder, may reduce energy expenditure.
Cardiovascular Disease Bipolar disorder has been associated with an approximately doubled risk of mortality from cardiovascular disease (CVD) compared with the general population (Westman et al., 2013). Risk factors for CVD that are elevated in people with bipolar disorder include hypertension, hyperlipidemia, and impaired endothelial function (Goldstein, Fagiolini, Houck, & Kupfer, 2009; Rybakowski, Wykretowicz, Heymann-Szlachcinska, & Wysocki, 2006).
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CVD may also be influenced by common comorbidities including cigarette smoking, heavy alcohol use, obesity, and insulin resistance, as well as the increased systemic inflammation seen during acute mood episodes. Among these risk factors, rates of abdominal obesity are significantly higher in women than in men with bipolar disorder (Gomes et al., 2013).
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Sexually Transmitted Diseases Impulsivity, hypersexuality, impaired judgment, and comorbid substance use disorders sometimes accompanying bipolar disorder place women at risk for ¨ sexually transmitted diseases (Ozcan, Boyacio˘glu, Enginkaya, Dinc¸, & Bilgin, 2014). Among patients with bipolar disorder and substance use disorders, over 75% reported high rates of sexual risk behaviors, with women more likely than men to report sex trading.
PSYCHOPHARMACOLOGIC CONSIDERATIONS FOR WOMEN WITH BIPOLAR DISORDER Agents approved by the Food and Drug Administration for the treatment of bipolar disorder, mania, or both include lithium, the anticonvulsant agents carbamazepine, lamotrigine and valproate, and the second-generation antipsychotic (SGA) agents aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. Of note given the relatively high prevalence of depressive episodes in women with bipolar disorder, mood stabilizers are generally more effective in treating and preventing mania than depression. Among mood stabilizing agents, lamotrigine appears to be relatively effective for treating and preventing bipolar depressive episodes (Goodwin et al., 2004). In the absence of mood stabilizing agents, antidepressants may precipitate mania (Valenti et al., 2012).
Mood Stabilizer Efficacy and Side Effects In general, women and men respond equally well to pharmacotherapy for bipolar disorder. Women, however, may respond to somewhat lower serum concentrations of lithium than men (Viguera, Baldessarini, & Tondo, 2001). Side effect considerations may be affected by gender. Among patients with bipolar disorder, women are more likely than men to fear weight gain and to identify it as the most worrisome medication side effect (Kriegshauser et al., 2010). Risperidone often causes hyperprolactinemia, sometimes resulting in galactorrhea, gynecomastia, menstrual abnormalities, sexual dysfunction, or all of these. Long-term prolactin elevation can reduce bone density (Meaney et al., 2004).
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Mood Stabilizers, Fertility, and Contraception Hyperprolactinemia from risperidone occasionally reduces fertility (Smith, Wheeler, Murray, & O’Keane, 2002). Valproate can predispose women to features of polycystic ovary syndrome (PCOS), including reduced ovulation and irregular menses (Hu et al., 2011). In addition, women with bipolar disorder have a higher prevalence of PCOS independently of the effects of valproate (Jiang, Kenna, & Rasgon, 2009). Women with bipolar disorder may be at high risk of unintended pregnancy. In a survey of 136 Brazilian women of childbearing age with bipolar disorder, 41% of study participants reported not using any contraception (Magalh˜aes, Kapczinski, & Kauer-Sant’Anna, 2009). There are significant drug–drug interactions between mood stabilizers and hormonal contraceptives. The enzyme-inducing mood stabilizers carbamazepine and oxcarbazepine increase clearance of combined oral contraceptive (COC) pills and transdermal patches, progestogen-only pills, and progestogen implants. By a different mechanism, lamotrigine may also reduce COC efficacy, although this is less well established (Sidhu, Job, Singh, & Philipson, 2006). Although some providers attempt to compensate by offlabel prescribing of higher-dose contraceptives, there is no confirmed dose range that assures adequate contraception. Alternate birth control methods include depot medroxyprogesterone acetate injections, copper intrauterine devices, and levonorgestrel-releasing intrauterine systems. Contraceptive agents may alter levels of mood stabilizers. Lamotrigine and valproate clearance increases substantially with use of estrogen-based contraceptives, such that plasma levels are considerably lower during the active phase of a contraceptive cycle than they are during the placebo phase (Herzog et al., 2009; Sidhu, Job, Singh, & Philipson, 2006). Women requiring these medications can consider nonestrogenic, including progestogen-only, contraception. Other factors influencing optimal contraceptive methods include sexual behavior patterns and ability to adhere to medication regimens. Women whose symptoms interfere with consistent daily pill use or preplanning for sexual encounters may benefit from longer-acting alternatives, particularly intrauterine devices (IUDs). In a study of 849 women with bipolar disorder using four types of contraception, women using IUDs were most likely to continue the method for at least 12 months (Berenson, Asem, Tan, & Wilkinson, 2011).
Mood Stabilizers, Pregnancy, and Breastfeeding Navigating pregnancy with bipolar disorder can be challenging, since both untreated symptoms and treatments pose risks. In most cases, risks of untreated symptoms outweigh risks of a carefully chosen medication regimen and appropriate monitoring. In Table 2, we summarize available data from
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• Right-sided cardiac defects • (0.05%–0.1%) • • Fetal nephrogenic diabetes insipidus (presenting as polyhydramnios, uterine enlargement, maternal shortness of breath) • Prematurity • Transient hypothyroidism • “Floppy baby” syndrome
Lithium
• •
• Pregnancy lowers serum level
• • • Neural tube defects (0.5%–1%) • • Possible increased bleeding risk due to • deficiency of Vitamin K-dependent clotting factors
• No systematic data
Pregnancy
Lamotrigine
Carbamazepine
Aripiprazole
Medication
Peripartum considerations
• Use in pregnancy based on risk/benefit analysis • Folate supplementation before and during pregnancy to reduce risk of neural tube defects • Ultrasound at 16–18 weeks gestation for exposure during period of neural tube formation (14–35 days after conception) • Vitamin K supplementation to newborn per pediatric recommendations 3.1%–21.1% of mother’s dose • Dose adjustment often needed during Increased platelet counts; apneic pregnancy due to increased clearance, with return to preconception levels episode, rash postpartum • Need to distinguish benign infant rash from Stevens-Johnson syndrome 0–30% of mother’s dose • Avoid period of cardiac formation Cyanosis, restlessness, muscle twitches, (days 18–55 after conception) when possible lethargy, hypothermia • Ultrasound, fetal echocardiography at 16–18 weeks gestation with early exposure • Monitor for polyhydramnios • Consider divided doses near term to reduce toxic peaks to newborn • Consider halving the dose at labor onset to reduce risk of maternal and neonatal toxicity • Risk of toxicity in breastfeeding babies increases with fever, dehydration (Continued on next page)
