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Bipolar I disorder occurs in approximately 1% of the adult population, and it affects women and men, equally. Women develop bipolar II disorder, bipolar depression, mixed mania, and a rapid-cycling course of illness more commonly than men and are at greater risk of such comorbid conditions as alcohol use problems, thyroid disease, medication-induced obesity, and migraine headaches. The treatment of bipolar disorder remains challenging. Although lithium reduces symptoms and prevents recurrence with good efficacy, a significant number of patients stop taking it. Furthermore, several anticonvulsants and antidepressants are prescribed off label for acute episodes and prophylaxis despite the lack of adequate research support. Psychotherapy may alleviate mania or depression and improve treatment compliance, yet its ability to prevent relapse remains uncertain. Changes throughout the reproductive cycle also have an impact on the onset and presentation of bipolar symptoms and the choice of treatment. This article provides an overview of common presentations and comorbidities, along with approaches to evaluation and treatment of women with bipolar disorder.
The lifetime prevalence of bipolar I disorder (BD I) has been estimated at 1.3% from Epidemiologic Catchment Area Study data.1 However, recent reports have suggested much higher prevalence rates, 3.7% to 6.4%, for bipolar spectrum disorders.2,3 Overall, BD I affects women and men equally,4 but bipolar II disorder (BD II), mixed episodes, bipolar depression, and a rapid-cycling course of illness occur more commonly in women.5–10
Bipolar disorder (BD) is a chronic condition with an average age of onset of 21 years.11 Although sex difference in age of onset has not been consistently observed, women appear over-represented in later-onset illness (45–49 years).4 Of greater concern, women face major delays in treatment, up to 11 years from onset, because of failure to diagnose, compared with a 7-year delay among men.12
The chance for relapse/recurrence of mania or depression is 37% within the first year of an episode,13 increasing to 87% at 5-year follow-up14 and affecting women and men equally.15,16 The costs related to treatment and loss of productivity from BD are substantial. An incident-based study estimated a total lifetime cost of BD in 1998 at $24 billion, and half the cost was attributed to loss of function/work status.17 Sex effects on mental health care costs were not mentioned.
The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)18 defines BD I as a clinical condition with recurrent mania, major depression, or mixed episodes (symptoms of mania/depression occurring together in a 1-week period). BD II is characterized by episodes of recurrent depression and hypomania.
Mania is a persistent, abnormally elevated, expansive or irritable mood for at least 1 week with symptoms of inflated self-esteem, excessive goal-directed activity, psychomotor agitation, distractibility, and poor judgment. Hypomanic episodes are shorter (4 days) and are characterized by increased creativity, productivity, and sociability or increased irritability that family/co-workers notice.
Severe mania may be accompanied by psychosis (delusional thoughts, hallucinations, disorganized speech/behavior), suicidality, and impaired judgment. Marked social/occupational dysfunction and psychosis distinguish mania from hypomania. Bipolar women appear to have fewer symptoms of psychosis19 and are hospitalized less often than men for mania,8,20,21 but these observations have not been found consistently.15,22,23
Depression is characterized by at least 2 weeks of low mood or diminished interest or enthusiasm, with neurovegetative changes, cognitive impairment, and altered functioning (see Bromberger review, this issue). Inpatient women have reported more total depressive episodes22,24 and were more likely than men to be hospitalized for depression..21 Bipolar depression is often associated with onset in childhood or early adulthood,25 psychosis,26 and increased suicide risk.4 Women often describe a seasonal pattern27 and atypical symptoms, such as weight gain, hypersomnia, and extremely low energy (leaden paralysis).28–30 Past depression predicts a 60% chance of a depressive recurrence and subsyndromal symptoms may persist in follow-up.31,32 Bipolar women frequently present with depression before mania,6 consistent with findings that up to 30% of outpatients with depression are only later diagnosed with BD.33,34 Failure to diagnose bipolar depression may lead to persistent illness, a more treatment-resistant illness, and increased risk of rapid cycling/cycle acceleration with unopposed antidepressants.
Mixed mania describes an episode in which symptoms of mania and depression occur daily for a week.18 It is characterized by agitation, refractory anxiety, intractable insomnia, suicidality, obsessions and impulses, hypersexuality,7 and a higher frequency of psychosis and suicidality compared with pure mania.35 Women are somewhat more likely than men to have mixed episodes,36,37 and women experience more depressive and fewer manic symptoms than men.7 On the other hand, the risk of suicide seems unrelated to gender.35 Individuals commonly experience an array of mood symptoms, including dysphoria – irritability and paranoia (contrast to euphoria and grandiosity),7,38 cyclothymia (numerous hypomanic and depressive symptoms that fail to meet full criteria for mania/depression), and agitated depression,39 that may be triggered by use of antidepressants without mood stabilizers.40
Rapid cycling refers to a pattern of 4 or more mood episodes occurring within a year.18 Episodes are separated by a mood switch to an opposite pole or by remission for 8 or more weeks. Rapid cycling occurs later in bipolar illness and is associated with increased rates of depression, suicidality,41 substance abuse, anxiety,42 and hypothyroidism.9 Some reports suggest a female to male ratio of 3:1,8 whereas others have found smaller but significant differences between women and men (30%, 17% respectively).43,44 Growing evidence indicates that antidepressants may trigger cycle acceleration and rapid cycling,45 with a greater likelihood in women than men.46 The risk of inducing mania from antidepressant withdrawal remains a concern, but is most likely avoided when mood stabilizers are used.
BD is associated with increased comorbid axis I illnesses: panic disorder/agoraphobia, social phobia, alcohol use, marijuana use, and, to a lesser degree, bulimia nervosa.47,48 A past history of sexual abuse is reported twice as often in women as men with BD (43% v 21%).49 Early extreme stressors predict early onset of BD, rapid cycling, increased suicide attempts, and post-traumatic stress disorder.49
Women with BD are at higher risk of alcohol abuse/dependence than are men with BD (odds ratios of 7.35, 2.77 respectively)50 and are more likely to have manic,51 depressive, and anxiety symptoms.52 Alcohol use disorders are also linked with polysubstance use, a family history of alcoholism, history of verbal abuse, and social phobia.50 Biologically, alcohol dehydrogenase activity and first-pass hepatic metabolism are lower in women than men, which result in higher blood alcohol levels and increased risk of alcohol toxicity.
Increased physical health problems and pain disorders occur in bipolar women.51 Hypothyroidism is twice as common in women as men with BD (23%, 12% respectively) and may contribute to a delayed response to treatment in bipolar depression.52,53 Lithium treatment and the presence of thyroid antibodies are associated with increased risk of thyroid failure.54
Although valproate appears to induce menstrual irregularities more frequently than lithium therapy, the association between valproate and polycystic ovarian syndrome in BD remains uncertain.55 Menstrual irregularities may also arise from non-pathological causes, hypothyroidism, hyperprolactinemia (triggered by certain atypical antipsychotics such as. risperidone), and eating disorders.55
An increased susceptibility to obesity and a drug-induced metabolic syndrome may be linked with valproate in bipolar women, who appear to develop hyperandrogenism and elevated leptin levels more frequently with it than with lithium.56 Bipolar inpatients have an increased prevalence of diabetes, which may be associated with a body mass index (BMI) equal to or greater than 25 when age, sex, and race-matched with the general population.57,58
Acquired immune deficiency syndrome (AIDS)-related dementia can present as secondary mania, with symptoms of irritability and cognitive slowing, whereas a lowered immune function has been associated with depression in human immunodeficiency virus (HIV).62 In fact, depressed women with HIV and CD4 counts less than 200 × 106/L have a significantly higher mortality rate (54%) than non-depressed HIV-positive women (21%) with similar counts.62 More complete reviews on the topic of BD and HIV, coronary artery disease, and cerebrovascular disease have been addressed.63–65
Regular assessment of women with BD is important in the primary care setting. The medical issues of bipolar women may be related to comorbid psychiatric or medical illnesses, medication toxicity or side effects, and life cycle factors.18 In addition, primary neurologic (multiple sclerosis, stroke, head trauma), pharmacologic (corticosteroid medications), infectious, toxic or metabolic causes may precipitate mania/depression and demand rapid intervention.66 Therefore, a complete assessment includes medical, psychiatric, alcohol/substance use, and family histories; inquiry about stressors; and screening for unusual beliefs and risk of harm to self or others. With patient permission, family members and significant others may be interviewed to clarify symptoms and subtle changes that the patient may be experiencing. A directed physical examination should focus on the neurological system and include regular weight measures, laboratory testing for complete blood count, electrolytes, renal and thyroid function (with lithium treatment), hepatic function (anticonvulsants), glucose and lipid profile, and baseline electrocardiogram (atypical antipsychotics). Periodic serum medication levels will be useful to guide dosing and monitor for compliance and toxicity.
Clinicians must develop a therapeutic alliance with the patient, watch for early changes in the patient’s clinical status, and educate patients and caregivers about bipolar illness in order to achieve better symptom control, fewer recurrences, enhanced treatment compliance, and earlier treatment of break-through symptoms.66–68 Prevention of Episodes
The only medications currently approved by the Food and Drug Administration (FDA) for bipolar prophylaxis are lithium4,69–72 and lamotrigine (bipolar depression prevention).72 Lithium is the single mood stabilizer that lowers suicide risk in bipolar patients.12,73,74 However, the effectiveness of long-term lithium prophylaxis is curtailed by high drop-outs from treatment75 due to medication intolerance and non-response. Furthermore, rapid discontinuation of lithium (<2 weeks) compared with gradual discontinuation (2–4 weeks) after sustained prophylaxis of 3.6 years usually results in recurrence in the first 6 to 12 months after stopping lithium.76
Other agents that have demonstrated efficacy for relapse prevention (albeit in fewer trials) are divalproex sodium,71 olanzapine,77 and possibly carbamazepine (more so for bipolar spectrum disorders).78 Divalproex sodium and carbamazepine may be more effective when combined with another anticonvulsant or with lithium, but the trade-off is more side effects.79
The drug absorption and bioavailability of drugs differ between women and men.80 Fat-soluble medications have a greater volume of distribution and longer half-life in women that lead to higher drug serum levels and prolonged clinical and adverse effects. Therefore, women may benefit from a lower initial dose, titrated according to side-effect tolerance and therapeutic effect, with the exception of acute mania in which dosing must be quickly optimized.
Lithium, valproic acid, chlorpromazine, and, more recently, the atypical antipsychotics (olanzapine, quetiapine, and risperidone) have been approved by the FDA for the treatment of mania. Alternative choices include carbamazepine and oxcarbazepine.81 The Texas Medication Algorithm for BD provides a helpful framework for decision making in the treatment of pure and mixed mania.82 The addition of valproate, risperidone or olanzapine to antimanic agents appears to effectively reduce mixed mania.19,78,83 Clozapine is a suitable alternative for refractory bipolar mania and bipolar psychosis84,85 and best managed under the supervision of a psychiatrist or medication group. Verapamil (calcium channel blocker) and aripiprazole (partial D2 and 5HT-1A agonist and 5HT2A antagonist) are novel agents with early evidence of efficacy for bipolar mania.86,87
In acute mania, mood must be stabilized quickly. This necessitates a rapid initiation and titration of an antimanic agent to achieve therapeutic range and possible add-on of an atypical antipsychotic or an adjunct agent, such as a benzodiazepine, for a brief period. Electroconvulsive therapy (ECT) remains a very appropriate option for bipolar psychosis, treatment resistance, severe mixed episode, or pregnancy, to induce rapid mood stabilization.88
Lithium, the combination of olanzapine and fluoxetine, and lamotrigine are appropriate first-line interventions to reduce depressive symptoms and prevent recurrence.89,90 Less treatment-responsive depression may require trial of a different mood stabilizer, a second mood stabilizer or atypical antipsychotic, or addition of an antidepressant.90 If this fails, ECT may be necessary. Use of antidepressants in BD must be undertaken with great caution. Antidepressant monotherapy is not indicated in bipolar illness because of a 4-fold risk of developing a manic switch.91 Newer findings indicate that all antidepressants have an equal likelihood of inducing cycle acceleration and manic-switching,78,91 despite past reports that suggested serotonin reuptake inhibitors92 and bupropion93 were less likely than tricyclic antidepressants to induce mania. If a mood stabilizer/antidepressant combination appears essential for bipolar depression, it is strongly recommended that the antidepressant be tapered after 3 to 6 months of remission.94
Possible triggers for rapid cycling, such as hypothyroidism and substance abuse, must be identified and addressed; unopposed antidepressants may need to be discontinued.40 A recent meta-analysis indicated less favorable responses to all rapid-cycling treatments.95 The pooled data on recurrence rates of antimanic medications were (from lowest to highest): lithium (2.1%/month), carbamazepine (2.9%/month), valproate (3.6%/month), lamotrigine (8.6%/month) and placebo (12%/month). Unfortunately, several reported outcomes were based on treatments that combined antimanic agents with antidepressants. Lithium, valproate, or lamotrigine are appropriate initial treatment choices.44 Other possibilities include adding another antimanic agent to more fully suppress cycling96 or switching to clozapine when monotherapy or combination therapy have failed.97
Renal, thyroid, and pregnancy status must be checked before starting lithium therapy. Serum drug levels and renal tests should be repeated after 5 days of initiation (earlier if toxicity suspected; therapeutic levels 0.4–1.0 mEq/L) with dose adjustments, and every 6 to 12 months upon stabilization.67 Sedation, tremor, renal dysfunction, weight gain, nausea, and vomiting are side-effects that may become very apparent with lithium toxicity. Medications such as thiazides, nonsteroidal anti-inflammatory agents, and angiotensin-converting enzyme inhibitors can alter renal excretion of lithium, especially with dehydration, older age, and renal impairment.98
Common side effects of divalproex sodium include nausea, weight gain, alopecia, hepatitis, thrombocytopenia, and, rarely, pancreatitis and require regular clinical monitoring.
Atypical antipsychotic medications such as quetiapine, risperidone, and olanzapine may cause such side effects as somnolence, dry mouth, akathisia, and increased liver transaminases. Significant weight gain (≥7% baseline weight) occurs in 40% of individuals on olanzapine, with the greatest increases experienced by those who were underweight at the start of treatment.99 Olanzapine-induced weight gain is also associated with elevated triglyercide levels.100 The weight increase with olanzapine is significantly greater than that with lithium and valproate and affects women more than men.100,101 The risk of glucose intolerance or new-onset diabetes is also increased with olanzapine treatment.101,102 Behavioral interventions effective for weight reduction include diet modification, dietician monitoring, weight loss defined as a treatment goal, and exercise. Although extrapyramidal side effects (tremor, rigidity, akathesia, bradykinesia, tardive dyskinesia, dystonia) are less common with atypical than typical antipsychotics, the risk of extrapyramidal side effects remains elevated in women, the elderly, and patients with affective disorders.
Lamotrigine successfully treats bipolar depressive symptoms at low to moderate doses.89 It causes nonserious rash in 7% to 10% of patients and precipitates Stevens-Johnson syndrome in 3/1000 cases. Rash reactions occur more frequently with early rapid dose escalation, in combination with valproate, and in adolescents.98 Patients must watch for the appearance of any rash while on lamotrigine, and they must stop the medication and seek immediate medical attention once a rash develops.
Carbamazepine is protein-bound and metabolized by the liver; the therapeutic plasma range is 4 to 12 micrograms/mL. Beyond 2 to 4 weeks of treatment, carbamazepine induces the cytochrome P 450 3A4 enzyme activity to triple its own clearance rate and cause drops in the plasma levels of other drugs (such as valproate) metabolized by the same cytochromes. Hepatitis, leukopenia, thrombocytopenia, rash, sedation, and ataxia are possible side effects. Hyponatremia has been reported with oxcarbazepine. Combination therapy with clozapine is not recommended, given the potential for bone marrow suppression.
Cognitive therapy,103 family focused treatment,104 and interpersonal therapy105 are useful adjuncts to pharmacotherapy for mood improvement, medication compliance, and restoration of social rhythms. Lam et al106 reported success with cognitive therapy in preventing bipolar relapse. Family-focused treatments reduce hospitalization and bipolar relapse107 and improve mood symptoms and medication adherence.104 Helpful contacts for patients, families, and providers include the National Institute of Mental Health (www.nimh.nih.gov), the National Alliance for the Mentally Ill (www.nami.org), and the Depression and Bipolar Support Alliance (www.dbsalliance.org).
Case reports and retrospective studies have explored the relationship between menstrual cycling and mood alterations.8 Although bipolar women describe significant mood changes during the menstrual cycle,108 no consistent pattern between menstrual cycle phase and the direction of mood switches has been detected.109
Bipolar recurrences occur in 45% to 50% of pregnancies,110,111 but with lithium prophylaxis the recurrence rate falls to 21%.112 Abrupt discontinuation of antimanic agents and a past history of 4 or more episodes are significantly associated with increased risk of recurrence.112,113 The risk of recurrence is 20% to 50% in women postpartum,114 and the risk of first-time hospitalization for bipolar illness is 7 times greater in the first month after delivery than in women who have not given birth.115,116 The failure to treat postpartum psychiatric conditions may result in worsening symptoms, more treatment-resistant illness, and impaired maternal social/occupational function, with adverse consequences for the newborn and offspring.117
Postpartum psychosis affects 1 to 2women per thousand after delivery115 and seems more closely linked to BD.116 It begins within 2 weeks of childbirth with symptoms of mood disturbance, confusion, delusional thinking, hallucinations, poor concentration, and impaired judgement/insight. This is a psychiatric emergency that requires complete screening for thoughts of harming self or others (possible increased risk of suicide and infanticide)117 and necessitates immediate treatment in a hospital setting with an antimanic agent or antipsychotic agent or ECT.
Ideally, women with BD will work with their health care providers when planning their families and develop a management approach before conception. An informed decision must incorporate a careful assessment of the risks and benefits of treatment during pregnancy and postpartum and consider the risks of fetal exposure to medications; the risks to the patient, family, and fetus of an untreated illness; and the substantial risk for relapse with discontinuation of treatment.117
Intrauterine death, structural malformations, growth retardation, neonatal toxicity, and neurobehavioral teratogenicity should all be considered in choosing medications.118 Strategies to minimize fetal exposure to pharmacotherapy include minimizing medications in the first trimester, monotherapy at the lowest effective dose, dividing daily doses to avoid high peak serum concentrations, avoiding medications with active metabolites.
Divalproex sodium and carbamazepine have greater teratogenic potential and are associated with increased risk of neural tube defects, craniofacial anomalies, cardiac defects, growth retardation, microcephaly, neonatal liver toxicity, and vitamin K deficiency (particularly with carbamazepine).119–121 Lithium remains an important treatment option because of fetal risks with maternal anticonvulsants.
The risk of Ebstein’s anomaly with lithium is 1 in 1000–2000 or a 10 to 20 times increased risk.122 Serum lithium levels should be checked at each trimester and doses adjusted accordingly, as hyperemesis, dehydration, elevated circulating volume, and volume shifts during delivery can alter serum drug levels. Lithium in pregnancy has also been associated with floppy baby syndrome (includes cyanosis and hypotonia), increased birth weight, neonatal hypothyroidism, and diabetes insipidus. Therefore, it is advisable to follow the pregnancy with level II/III ultrasounds in the second and third trimesters. Olanzapine use in pregnancy has been associated with gestational diabetes, eclampsia, meconium aspiration, and postmature birth.123 ECT appears to be an effective and safe alternative treatment for bipolar episodes in pregnancy.124 Omega-3 fatty acids continue to be studied for their mood-stabilizing effects and may be a potential treatment option in pregnancy.125,126 Please refer to Wisner et al118 for an approach to antidepressants in pregnancy.
Chaudron et al119 and the American Academy of Pediatrics127 extensively reviewed bipolar medications in breastfeeding. Lithium is generally to be avoided,127 whereas valproate or carbamazepine appear compatible, but may cause sedation in neonates/infants.121,127 Data on antipsychotics in breastfeeding are limited and thus far, adverse events have not been reported.119,128
Cerebrovascular disease and dementia are common neurologic conditions in late-life that bring changes in mood and behavior in bipolar patients. Even though menopause is defined by an elevated follicular stimulating hormone level with low estradiol levels and both perimenopause and menopause have been associated with bipolar exacerbations,110 agitated depression and psychotic mood episodes,129–131 the correlation between gonadal hormones and bipolar mood symptoms is unclear. Therefore, research is essential to explore the effect of gonadal hormones on BD.
In summary, women with BD are more likely than men to have BD II symptoms, depression, mixed episodes, and rapid cycling and are at increased risk of alcohol use disorders, panic disorder, social phobia, and eating disorders. Thyroid disease, menstrual irregularities, obesity, and migraines are other common comorbid conditions that affect bipolar women. Choice of treatment may be dictated by the illness subtype, other medical and psychiatric symptoms, presence of alcohol/substance use, episode acuity (psychosis, suicidality), medication side effect profile, and past treatment responses. Pregnancy and postpartum are times of increased vulnerability to onset or recurrence of illness, and it is preferable to have a planned treatment approach even before conception.
Under ideal settings, the woman with BD will be managed by close collaboration with all her providers. The psychiatrist, psychotherapist, and primary care providers must interact to quickly identify and treat acute episodes, prevent recurrences, and minimize psychiatric and medical comorbidities. The goal is to restore and maintain the bipolar woman’s function at home, at work, and in the community.
Dr. Sit is supported in part by a Young Investigator Award from the National Alliance for Research in Schizophrenia and Depression.