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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 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 comorbidi- ties. 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 un- derstanding 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
476 L. J. Miller et al.
Bipolar disorder is a leading cause of disability worldwide (Merikan- gas 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 high- risk 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 Associ- ation, 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 clini- cal presentation, reproductive cycle influences, sexuality, contraception, and medical comorbidities. We review considerations for pharmacotherapy, psy- chotherapy 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: Cumu- lative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Li- brary, OvidMD, PsycINFO, and PubMed. We prioritized inclusion of findings from randomized, double-blind, prospective controlled studies and meta- analyses 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 prospec- tive controlled studies. We included pilot studies and case series when they represented promising new approaches to understanding and treating bipo- lar disorder in women, when they shed light on potentially clinically impor- tant 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 de- pressive episodes (Altshuler, Kupka, & Hellemann, 2010; Nivoli, Pacchiarotti, & Rosa, 2011). Mixed episodes, in which both manic and depressive symp- toms 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
Bipolar Disorder in Women 477
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 night- time sleep (Benazzi, 2003; Kawa, Carter, & Joyce, 2005). During manic episodes, fewer women than men report problem behaviors, hyperactiv- ity, 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, Ash- man, 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 men- strual 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 discon- tinue mood stabilizing medications have high recurrence rates, as well as
478 L. J. Miller et al.
shorter time to recurrence and considerably more time ill compared with pregnant women who maintain medication (Viguera et al., 2007). Recur- rence risk is especially high for women who discontinue mood stabilizing medications abruptly rather than gradually, and for women who take antide- pressants. 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, how- ever, is a time when women are especially likely to consider discontinuing medication.
Fetal risks associated with untreated bipolar disorder may include pre- mature delivery and low birth weight (Lee & Lin, 2010). Additional risks of untreated mood episodes during pregnancy are high-risk impulsive behav- iors, poor self-care, addictive substance use, and suicide attempts.
Postpartum
The risk of recurrence of a bipolar mood episode is significantly higher post- partum 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 (Free- man 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 in- fluences on postpartum relapse include sleep deprivation, circadian rhythm disruption, new stressors, and social role transitions.
For women with new-onset depressive episodes postpartum, distin- guishing bipolar from unipolar depression can be challenging. In one large study (Azorin et al., 2012), when first lifetime depressive episodes were post- partum, they included increased rates of hypomanic and psychotic symp- toms, with higher rates of subsequent bipolar diagnosis. In another study, depression onset within 2 weeks after delivery was associated with sub- sequent development of bipolar disorder (Munk-Olsen, Laursen, Meltzer- Brody, Mortensen, & Jones, 2012). In Table 1, we summarize clinical indica- tors 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.
Bipolar Disorder in Women 479
TABLE 1 Clinical Indicators of Possible Bipolar Disorder for Women With New-Onset Post- partum Depression
Item Increased likelihood of bipolar disorder
History 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
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 hallucina- tions, 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 nonpostpar- tum psychotic mood episodes (Wisner, Peindl, & Hanusa, 1994). Tempo- rary 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 necessi- tates 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,
480 L. J. Miller et al.
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 symp- toms, although not major depressive episodes, in perimenopausal women with unipolar depression. It is not known whether this is the case for bipo- lar 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 dysregu- lation 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).
Bipolar Disorder in Women 481
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).
Sexually Transmitted Diseases
Impulsivity, hypersexuality, impaired judgment, and comorbid substance use disorders sometimes accompanying bipolar disorder place women at risk for sexually transmitted diseases (Özcan, Boyacioğlu, Enginkaya, Dinç, & 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 an- tipsychotic (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).
482 L. J. Miller et al.
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 preg- nancy. In a survey of 136 Brazilian women of childbearing age with bipolar disorder, 41% of study participants reported not using any contraception (Magalhães, Kapczinski, & Kauer-Sant’Anna, 2009).
There are significant drug–drug interactions between mood stabilizers and hormonal contraceptives. The enzyme-inducing mood stabilizers car- bamazepine and oxcarbazepine increase clearance of combined oral con- traceptive (COC) pills and transdermal patches, progestogen-only pills, and progestogen implants. By a different mechanism, lamotrigine may also re- duce COC efficacy, although this is less well established (Sidhu, Job, Singh, & Philipson, 2006). Although some providers attempt to compensate by off- label 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 sex- ual 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 disor- der 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 un- treated symptoms outweigh risks of a carefully chosen medication regimen and appropriate monitoring. In Table 2, we summarize available data from
T A
B L E
2 E ff e ct
s o f M
o o d
St ab
il iz
in g
M e d ic
at io
n s
D u ri n g
P re
g n an
cy an
d B
re as
tf e e d in
g
M e d ic
at io
n P re
g n an
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re as
tf e e d in
g (i n fa
n t e x p o su
re le
v e l∗
; re
p o rt e d
ad v e rs
e e ff e ct
s∗ ∗ )
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tu m
co n si
d e ra
ti o n s
A ri p ip
ra zo
le •
N o
sy st
e m
at ic
d at
a •
< 0 .7
% o f m
o th
e r’ s
d o se
• n o n e , b u t li m
it e d
d at
a •
U se
in p re
g n an
cy b as
e d
o n
ri sk
/b e n e fi t
an al
y si
s C ar
b am
az e p in
e •
N e u ra
l tu
b e
d e fe
ct s
(0 .5
% – 1 %
) •
P o ss
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in cr
e as
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b le
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g ri sk
d u e
to d e fi ci
e n cy
o f V
it am
in K
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cl o tt in
g fa
ct o rs
• 0 – 2 .6
m g /L
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io n
• T ra
n si
e n t m
il d
li v e r
fu n ct
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ab n o rm
al it ie
s; p o o r
su ck
; v o m
it in
g
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m e n ta
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re d u ce
ri sk
o f
n e u ra
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at 1 6 – 1 8
w e e k s
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re d u ri n g
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4 – 3 5
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m e n ta
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cr e as
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to in
cr e as
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, w
it h
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rn to
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co n ce
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h t- si
d e d
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– 0 .1
% )
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si p id
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n si
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m •
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sy n d ro
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o f m
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le th
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v o id
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rm at
io n
(d ay
s 1 8 – 5 5
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p ti o n )
w h e n
p o ss
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• U
lt ra
so u n d , fe
ta l e ch
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g ra
p h y
at 1 6 – 1 8
w e e k s
g e st
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n w
it h
e ar
ly e x p o su
re •
M o n it o r
fo r
p o ly
h y d ra
m n io
s •
C o n si
d e r
d iv
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d o se
s n e ar
te rm
to re
d u ce
to x ic
p e ak
s to
n e w
b o rn
• C o n si
d e r
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v in
g th
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b o r
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t to
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al an
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al to
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k o f to
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as tf e e d in
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ti n
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n ex
t p a
ge )
483
T A
B L E
2 E ff e ct
s o f M
o o d
St ab
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in g
M e d ic
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ti n
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)
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g n an
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re as
tf e e d in
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p o rt e d
ad v e rs
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s∗ ∗ )
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tu m
co n si
d e ra
ti o n s
O la
n za
p in
e •
N o
in cr
e as
e d
ri sk
o f an
o m
al ie
s b as
e d
o n
p ro
sp e ct
iv e , co
n tr o ll e d
st u d y
o f
SG A
s∗ ∗∗
an d
re g is
tr y
d at
a; m
ay in
cr e as
e ri sk
o f g e st
at io
n al
d ia
b e te
s
• 0 .3
% – 4 %
o f m
o th
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d o se
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d at
io n , p o o r
su ck
, sh
ak in
g , ra
sh ,
d ia
rr h e a,
so m
n o le
n ce
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o n it o r
w e ig
h t an
d g lu
co se
• Se
d at
io n
m ay
in te
rf e re
w it h
p ar
e n ti n g
Q u e ti ap
in e
• N
o in
cr e as
e d
ri sk
o f an
o m
al ie
s b as
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o n
a p ro
sp e ct
iv e , co
n tr o ll e d
st u d y
o f
SG A
s∗ ∗∗
• Lo
w e st
p la
ce n ta
l p as
sa g e
am o n g
SG A
s∗ ∗∗
• 0 .0
9 %
– 0 .4
3 %
o f m
o th
e r’ s
d o se
• N
o n e , b u t li m
it e d
d at
a •
M o n it o r
w e ig
h t an
d g lu
co se
• Se
d at
io n
m ay
in te
rf e re
w it h
p ar
e n ti n g
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p e ri d o n e
• N
o in
cr e as
e d
ri sk
o f an
o m
al ie
s b as
e d
o n
a p ro
sp e ct
iv e , co
n tr o ll e d
st u d y
o f
SG A
s∗ ∗∗
• 0 .8
4 %
– 4 .3
% o f m
o th
e r’ s
d o se
• N
o n e , b u t li m
it e d
d at
a •
M ay
re d u ce
fe rt il it y
• M
o n it o r
w e ig
h t an
d g lu
co se
• Se
d at
io n
m ay
in te
rf e re
w it h
p ar
e n ti n g
V al
p ro
at e
• N
e u ra
l tu
b e
d e fe
ct s
(1 %
– 5 %
) an
d o th
e r
p h y si
ca l an
o m
al ie
s •
In tr au
te ri n e
g ro
w th
re ta
rd at
io n
• N
e o n at
al h y p o g ly
ce m
ia •
N e o n at
al w
it h d ra
w al
• M
ay in
cr e as
e ri sk
o f g e st
at io
n al
d ia
b e te
s
• In
fa n t se
ru m
co n ce
n tr at
io n
0 .9
% – 4 0 %
o f m
o th
e r’ s
• N
o n e
• F o la
te su
p p le
m e n ta
ti o n
b e fo
re an
d d u ri n g
p re
g n an
cy •
K e e p
d o se
< 1 0 0 0
m g /d
ay w
h e n
p o ss
ib le
as ri sk
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Bipolar Disorder in Women 485
human studies of the effects of mood stabilizing agents during pregnancy and lactation. Key considerations include the following:
• Valproate increases the risk of neural tube defects, developmental impair- ments, and hepatotoxicity. Another mood stabilizing medication can be substituted if effective. If not, risk can be reduced by using the lowest ef- fective dose and administering folate. Dosing can be guided by free serum levels; total serum levels are less reliable due to pregnancy-linked changes in the bound (inactive) fraction.
• Lithium increases the risk of fetal nephrogenic diabetes insipidus, neona- tal toxicity, and transient neonatal hypothyroidism, and may increase the risk of premature labor and cardiac anomalies. Another mood stabiliz- ing medication can be substituted if effective. When lithium is used, serum levels should be monitored approximately once per trimester; pregnancy-linked pharmacokinetic changes such as increased glomerular filtration rate and plasma volume can reduce lithium levels and necessitate dose increases. Postpartum, the dose may need to be promptly lowered to the prepregnancy therapeutic dose to avoid maternal toxicity. While most breastfeeding babies do not experience adverse effects from ma- ternal lithium use, they may develop toxicity, especially if they become dehydrated.
• Lamotrigine is a reasonable alternative to valproate or lithium. Data from the North American AED Pregnancy Registry previously led to concerns about increased risk of cleft palate in babies after first trimester lamotrigine exposure (Holmes et al., 2008). A case-control study surveying 3.9 million births from 19 registries did not confirm this association (Dolk et al., 2008), however, nor did subsequent studies (Cunnington et al., 2011; Mølgaard-Nielsen & Hviid, 2011). No increased neurodevelopmental abnormalities have been found in children exposed in utero (Cummings, Stewart, Stevenson, Morrow, & Nelson, 2011). Due to pharmacokinetic changes, serum lamotrigine levels are reduced during pregnancy by 50%–60% on average, with considerable individual variation. This can be addressed by obtaining a reference serum lamotrigine level before pregnancy or as early in pregnancy as possible, then monitoring as needed and increasing the dose by 20%–25% if the serum level falls below the reference level. The prepregnancy dose can be resumed postpartum (Sabers, 2012). Breastfeeding while taking lamotrigine is relatively contraindicated due to comparatively high infant serum levels, a paucity of large-scale systematic data, and case reports of infant adverse effects.
• The SGAs olanzapine, quetiapine, and risperidone are also reasonable alternatives. Among them, risperidone has the greatest risk of reducing fertility, olanzapine has the greatest likelihood of contributing to risk of gestational diabetes mellitus and excessive weight gain, and quetiapine
486 L. J. Miller et al.
poses the greatest risk of sedation. Even nighttime sedation can be prob- lematic for women who need to be sufficiently alert when caring for their babies.
If a patient chooses to discontinue medications due to pregnancy or a wish to conceive, tapering poses less risk of relapse than abrupt discontin- uation (Viguera et al., 2007). Resuming medication immediately postpartum should be considered. Patient factors that may reduce the risks associated with medication discontinuation include the following:
• Excellent insight, including ability to recognize triggers and early warning signs of mood episodes, and willingness to seek help promptly if those occur.
• Excellent social support by others who are aware of the patient’s disorder and will assist her in seeking help for early symptoms.
• BD-II disease with no history of suicidal thoughts or behaviors, psychotic symptoms, or dangerous impulsiveness.
OTHER SOMATIC THERAPIES
Electroconvulsive therapy (ECT) is an effective treatment for acute bipolar mood episodes. Protocols of ECT can be modified to reduce risks during pregnancy (Miller, 1994).
Phototherapy, consisting of exposure to bright light for specified periods of time daily, can alleviate bipolar depression, especially seasonal depres- sion as occurs more frequently in women. Phototherapy, however, induces agitation, mixed states, or both in some patients with bipolar disorder. This risk can be reduced by shortening exposure duration (e.g. from the usual 20–40 minutes to 15 minutes) and by shifting from morning to midday timing (Sit, Wisner, Hanusa, Stull, & Terman, 2007).
PSYCHOTHERAPY
Psychotherapies effective for bipolar disorder include cognitive-behavioral therapy (CBT), interpersonal and social rhythm therapy (IPSRT), and family- focused therapy (FFT). CBT focuses on identifying and changing maladap- tive thought and behavior patterns that influence mood symptoms. FFT aims to promote family understanding of the illness and its precipitants, reduce hostile or critical interactions, and improve communication skills (Morris, Miklowitz, & Waxmonsky, 2007). The aim of IPSRT is to regulate social
Bipolar Disorder in Women 487
TABLE 3 Brief Interventions to Improve and Maintain Mental Health for Women With Bipolar Disorder Across the Reproductive Cycle
Reproductive/life cycle stage Intervention
Puberty/menarche • Help girls identify triggers for their mood episodes, such as erratic sleep or substance use
• Maintain an empathic stance about the difficulties in resisting negative peer pressure, including encouragement when patients succeed in doing this
• Encourage depressed girls to focus on problem-solving rather than ruminative responses to stress
• Educate parents that hostile and/or critical communication can trigger mood episodes
• Foster acceptance of the diagnosis by demonstrating an understanding of the challenge of identity formation in the face of mental illness
Premenstrual • Encourage prospective daily symptom charting so that patients can learn their symptom patterns and predict high-risk times
• Recommend proactive planning for high-risk times, such as reducing difficult projects or deadlines while premenstrual when possible
• Educate family members about cyclic mood changes and their effects on interpersonal interactions
Perinatal • Counter unrealistic and overly perfectionistic expectations about labor, delivery, and motherhood
• Help women anticipate postpartum disruptions in circadian and social routines, and plan accordingly
• Emphasize the importance of at least several hours of uninterrupted sleep daily; encourage women to proactively ask others for nighttime help with baby care.
• Foster family collaboration to maintain maternal self-care, promoting adequate maternal nutrition, adult socialization, and breaks from child care
Perimenopausal • Address sleep disruption from night sweats and other factors • Help women address losses and role transitions
Sources: Coville, Miklowitz, Taylor, & Low, 2008; Hankin & Abramson, 2002; Schmidt, Murphy, Haq, Rubinow, & Danaceau, 2004.
and circadian rhythms (Frank, Swartz, & Boland, 2007). Each of these psy- chotherapies alleviates symptoms, speeds recovery from acute episodes, re- duces relapse rates, and improves interpersonal functioning (Frank, Swartz, & Boland, 2007; Miklowitz et al., 2007).
Stress and erratic sleep patterns are frequent triggers of bipolar mood episodes, while social support and exercise can reduce recurrence (Kil- bourne et al., 2007; Weinstock & Miller, 2010). Even without formal psy- chotherapy, clinicians can help women figure out practical ways to achieve predictable sleep schedules, incorporate exercise into their lives, manage stress, and negotiate for needed support. In Table 3, we summarize psy- chosocial interventions that clinicians can facilitate at different stages of the female reproductive cycle.
488 L. J. Miller et al.
NUTRITIONAL AND HERBAL SUPPLEMENTS
Two key nutrients that affect mood are omega-3 essential fatty acids (n- 3 EFA) and iron. A meta-analysis of studies to date finds that n-3 EFA supplements are effective in reducing bipolar depressive, but not manic symptoms (Sarris, Mischoulon, & Schweitzer, 2012). The efficacy of n-3 EFA supplements has not yet been clearly established for perinatal depressive episodes. In the largest randomized controlled trial to date, Makrides and colleagues (2010) found no significant differences in depressive symptoms up to 6 months postpartum in women receiving n-3 EFA supplements versus placebo. This may be because the n-3 EFA component used in that study, however, was docosahexaenoic acid (DHA) without eicosapentaenoic acid (EPA); in a meta-analysis (Martins, 2009) EPA but not DHA had efficacy for depression. Congruent with this possibility, Su and colleagues (2008) found in a randomized controlled trial that n-3 EFA supplements containing both DHA and EPA reduced depressive symptoms significantly more than placebo for pregnant women. In combination with aspirin or anticoagulants, n-3 EFA can reduce platelet aggregation, but it is rare for this to result in clinically significant increased bleeding (Larson et al., 2008; McClaskey & Michalets, 2007). Overall, the risk–benefit ratio of mercury-free sources of n-3 EFA supplementation is likely favorable.
Iron deficiency may increase vulnerability to mood episodes by lowering stress tolerance and inducing fatigue (Vahdat Shariatpanaahi, Vahdat Shariat- panaahi, Moshtaaghi, Shahbaazi, & Abadi, 2007). It is not known, however, whether iron supplementation reduces risk of depressive episodes. Other nutritional or herbal supplements have not shown consistent efficacy for treating bipolar disorder.
SUMMARY AND CLINICAL IMPLICATIONS
Understanding sex, gender, and reproductive influences on bipolar disorder can inform optimal treatment of women. The expressions of bipolar disorder that are more common in women—mixed episodes and a predominance of depressive symptoms—can be more subtle and therefore more difficult to detect, accounting for gender-linked delays in diagnosis and treatment initiation. Knowing this can lead to enhanced efforts to screen for bipolar disorder in girls and women who present with depressive symptoms, have a family history of bipolar disorder, or both. Awareness that a subset of women with bipolar disorder experience symptom exacerbation linked to specific menstrual cycle phases can promote prospective daily symptom charting for women in whom this pattern is suspected. Similarly, checking for seasonal patterns of mood episodes, which predominate in women, can help identify patients who may benefit from phototherapy.
Bipolar Disorder in Women 489
Understanding the influence of bipolar disorder on heightened risk of unprotected sex and unintended pregnancy highlights the importance of incorporating discussions of sexuality and family planning within medical and gynecologic care of women with mood disorders. Women who wish to use contraception can be guided toward choices compatible with the use of their mood-stabilizing medications. Women planning pregnancies can be advised about the effects of some mood-stabilizing medications on fertility. They can benefit from balanced, evidence-based consultation about perinatal risks of their illness and of their medications, and guidance about strategies to reduce risks.
At perimenopause, the possibility of precipitating mania can be taken into account when weighing the risks and benefits of estrogen or antide- pressant therapy for vasomotor symptoms. Recognizing the potential influ- ence of perimenopause and midlife role transitions on increasing depressive symptoms in women with bipolar disorder can lead to necessary treatment adjustments.
Research findings have elucidated the marked influence of circadian rhythms, social interactions, stressors, and sociocultural gender roles on the course of bipolar disorder in women across the lifespan. This underscores the central role of psychotherapies, supportive counseling, or both to help women create relatively predictable routines, prioritize self-care, garner so- cial support, pursue meaningful social roles, problem solve, and maintain self-esteem.
FUTURE DIRECTIONS
Current research is increasingly shedding light on the mechanisms of gender and reproductive influences on mood disorders. Studies are underway to elucidate the impact of inflammatory processes, hormonal regulation of neu- rotransmitter functioning, genetic vulnerability to environmental stressors, and sociocultural gender roles. Research is also enhancing our understand- ing of intergenerational influences of mood disorders via epigenetic and behavioral effects on fetal and neonatal development.
A developmental view of mood disorders across the male and female life cycles may ultimately deepen our understanding of biopsychosocial influ- ences on mood in general. Before puberty, boys and girls have approximately the same rates of mood disorders. At about midpuberty, rates of unipolar depression substantially increase in girls relative to boys, and they remain elevated in women relative to men at least through the midfifties (Kessler, McGonagle, Swartz, Blazer, & Nelson, 1993). In most, although not all studies and meta-analyses, rates of depression in women continue to exceed those in men throughout the rest of the lifespan as well (Cairney & Wade, 2002; Chou & Cheung, 2013; Copeland et al., 2004; Jang, Kim, & Chiriboga, 2011;
490 L. J. Miller et al.
Kuehner, 2003; Leach, Christensen, Mackinnon, Windsor, & Butterworth, 2008; Sonnenberg, Beekman, Deeg, & van Tilburg, 2000). Research eluci- dating this relative female vulnerability to unipolar but not bipolar disorder, and the relative female vulnerability to depressive symptoms within bipolar disorder, may help explain genetic, epigenetic, hormonal, and sociocultural influences on normal as well as psychopathologic mood states in both gen- ders (Goldstein, Handa, & Tobet, 2014; Kendler & Gardner, 2014; Kendler, Myers, & Prescott, 2005; Kendler, Thornton, & Prescott, 2001; Uddin, Sipahi, Li, & Koenen, 2013).
Treatment advances are emerging in the realms of neuroprotection, neuromodulation, and psychotherapy. Treatment modalities being actively investigated include transcranial magnetic stimulation, vagus nerve stimula- tion, and deep brain stimulation. In psychotherapy research, a key question is whether any form of psychotherapy is effective enough to obviate the need for medication in patients with BD-II, which would be especially helpful for pregnant women. To date there are no randomized controlled studies of psychotherapy as monotherapy for BD-II. Based on pilot data, however, IP- SRT may warrant further study. For example, Swartz, Frank, Frankel, Novick, and Houck (2009) administered 12 weekly sessions of IPSRT to 17 study par- ticipants with BD-II and a current major depressive episode; 41% achieved more than 50% reduction of depressive symptom scores without an increase in mania scores without medication. Other efforts are directed at reducing treatment burden: the time, expense, and logistics of attending therapy ses- sions. Treatment burden may be especially problematic for women who are postpartum, acutely depressed, or both. Technology-enabled tools to facili- tate IPSRT and CBT are being developed to help access.
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