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B. Demographic and Psychosocial Factors

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1. Gender

A number of issues related to gender must be considered when treating patients with bipolar disorder. Hypothyroidism is more common in women, and women may be more susceptible to the antithyroid effects of lithium (80). Additionally, rapid cycling is more common in women (81, 82). Treatment with antipsychotics and, to a lesser extent, SSRIs may elevate serum levels of prolactin and result in galactorrhea, sexual dysfunction, menstrual disorders, and impaired fertility (83, 84).

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2. Pregnancy

Because many medications used to treat bipolar disorder are associated with a higher risk of birth defects, the psychiatrist should encourage effective contraceptive practices for all female patients of childbearing age who are receiving pharmacological treatment (85, 86). Since carbamazepine, oxcarbazepine, and topiramate increase the metabolism of oral contraceptives, women taking these medications should not rely on oral contraceptives for birth control (87–89). This effect does not occur with other medications used to treat bipolar disorder.

Multiple clinical issues arise in relationship to pregnancy in bipolar disorder patients. In order to permit discussion of the risks and benefits of therapeutic options, a pregnancy should be planned in consultation with the psychiatrist whenever possible. Because of the higher genetic risk for bipolar disorder (90–92), patients with bipolar disorder who are considering having children may also benefit from genetic counseling (22).

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a) Continuing/discontinuing medications

Around the time of pregnancy, the risks and benefits of continuing versus discontinuing treatment require the most thoughtful judgment and discussion among the patient, the psychiatrist, the obstetrician, and the father. Specific options include continuing medication throughout pregnancy, discontinuing medications at the beginning of pregnancy or before conception, and discontinuing the medication only for the first trimester.

In clinical decision making, the potential teratogenic risks of psychotropic medications must be balanced against the risk of no prophylactic treatment, with the attendant risks of illness (93). Although the course of bipolar disorder during pregnancy is still unclear, some evidence suggests that pregnancy does not alter the rate of mood episodes compared with other times (94). However, in patients who have been stable on a regimen of lithium, the rate of recurrent mood episodes is clearly increased by lithium discontinuation, particularly when discontinuation is abrupt (94). Should the decision be made to discontinue medication, the woman should be advised about the potentially greater risk of mood episode recurrence with rapid discontinuation of lithium (and possibly other maintenance agents) compared with a slower taper over many weeks (95).

Although direct evidence of a negative effect of untreated psychiatric disorders on fetal development is lacking, antenatal stress, depression, and anxiety are linked with a variety of abnormalities in newborns (96–101). Additionally, during a manic episode, women are at risk of increasing their consumption of alcohol and other drugs, thus conferring additional dangers to the fetus.

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b) Prenatal exposure to medications

First-trimester exposure to lithium, valproate, or carbamazepine is associated with a greater risk of birth defects. With lithium exposure the absolute risk for Ebstein's anomaly, a cardiovascular defect, is 1–2 per 1,000. This is approximately 10–20 times greater than the risk in the general population (102). Exposure to carbamazepine and valproate during the first trimester is associated with neural tube defects at rates of up to 1% and 3%–5%, respectively (85). Both carbamazepine and valproate exposure have also been associated with craniofacial abnormalities (103, 104). Other congenital defects that have been observed with valproate include limb malformations and cardiac defects (104). Little is known about the potential teratogenicity of lamotrigine, gabapentin, or other newer anticonvulsants.

No teratogenic effects have been demonstrated with tricyclic antidepressants. Near term, however, their use has been associated with side effects in the neonate (105). The SSRIs seem to be relatively benign in their risks to exposed fetuses (106), with safety data being strongest for fluoxetine and citalopram. Although data with bupropion, mirtazapine, nefazodone, trazodone, and venlafaxine are limited (105), none of the newer antidepressants has been shown to be teratogenic (106, 107). Nonetheless, caution must be exercised if they are prescribed to treat bipolar depression in pregnant women (93).

Antipsychotic agents may be needed to treat psychotic features of bipolar disorder during pregnancy, but they may also represent an alternative to lithium for treating symptoms of mania (105). High-potency antipsychotic medications are preferred during pregnancy, since they are less likely to have associated anticholinergic, antihistaminergic, or hypotensive effects. In addition, there is no evidence of teratogenicity with exposure to haloperidol, perphenazine, thiothixene, or trifluoperazine (105). When high-potency antipsychotic medications are used near term, neonates may show extrapyramidal side effects, but these are generally short-lived (108). To limit the duration of such effects, however, long-acting depot preparations of antipsychotic medications are not recommended during pregnancy (105). For newer antipsychotic agents such as risperidone, olanzapine, clozapine, quetiapine, and ziprasidone, little is known about the potential risks of teratogenicity or the potential effects in the neonate.

The risk of teratogenicity with benzodiazepines is not clear (108). Early studies, primarily with diazepam and chlordiazepoxide, suggested that first-trimester exposure may have led to malformations, including facial clefts, in some infants. Later studies showed no significant increases in specific defects or in the overall incidence of malformations (108). A recent meta-analysis of the risk of oral cleft or major malformations showed no association with fetal exposure to benzodiazepines in pooled data from cohort studies, but a greater risk was reported on the basis of pooled data from case-control studies (109). In general, however, teratogenic risks are thought likely to be small with benzodiazepines (105). Near term, use of benzodiazepines may be associated with sedation in the neonate. Withdrawal symptoms resulting from dependence may also be seen in the neonate (108). As a result, if benzodiazepines are used during pregnancy, lorazepam is generally preferred (105).

ECT is also a potential treatment for severe mania or depression during pregnancy (110). In terms of teratogenicity, the short-term administration of anesthetic agents with ECT may present less risk to the fetus than pharmacological treatment options (111). The APA Task Force Report on ECT contains additional details on the use of ECT during pregnancy (110).

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c) Prenatal monitoring

Women who choose to remain on regimens of lithium, valproate, or carbamazepine during pregnancy should have maternal serum -fetoprotein screening for neural tube defects before the 20th week of gestation, with amniocentesis as well as targeted sonography performed for any elevated -fetoprotein values (105). Women should also be encouraged to undergo high-resolution ultrasound examination at 16–18 weeks gestation to detect cardiac abnormalities in the fetus. Since hepatic metabolism, renal excretion, and fluid volume are altered during pregnancy and the perinatal period, serum levels of medications should be monitored and doses adjusted if indicated. At delivery, the rapid fluid shifts in the mother will markedly increase lithium levels unless care is taken to either lower the lithium dose, ensure hydration, or both (112). Discontinuing lithium on the day of delivery is probably not necessary and may be unwise given the high risk for postpartum mood episodes and the greater risk of recurrence if lithium is discontinued in women with bipolar disorder (94, 112).

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d) Postpartum issues

The postpartum period is consistently associated with a markedly greater risk for relapse into mania, depression, or psychosis. For women with bipolar disorder, the rate of postpartum relapse is as high as 50% (86, 94). Women who have had severe postpartum affective episodes in the past are at highest risk to have another episode of illness after subsequent pregnancies. Despite a paucity of studies, it is generally considered that prophylactic medications such as lithium or valproate may prevent postpartum mood episodes in women with bipolar disorder (113). Also, since changes in sleep are common in the postpartum period, women should be educated about the need to maintain normal sleep patterns to avoid precipitating episodes of mania.

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e) Infant medication exposure through breast-feeding

All medications used in the treatment of bipolar disorder are secreted in breast milk in varying degrees, thereby exposing the neonate to maternally ingested medication (114). However, as with the risks of medications during pregnancy, risks of breast-feeding with psychotropic medications must be weighed against the benefits of breast-feeding (115, 116). Because lithium is secreted in breast milk at 40% of maternal serum concentration, most experts have recommended against its use in mothers who choose to breast-feed (105). Fewer data on breast-feeding are available for carbamazepine and valproate. Although it is generally considered safe, potential risks should always be considered. Little is known about lamotrigine exposure in breast-fed neonates; however, levels in the infant may reach 25% of maternal serum levels (117). Consequently, the potential for pharmacological effects, including a risk for life-threatening rash, should be taken into consideration (118). With other psychotropic medications (including antipsychotics, antidepressants, and benzodiazepines), there are few reports of specific adverse effects in breast-feeding infants. Nonetheless, these drugs are found in measurable quantities in breast milk and could conceivably affect central nervous system functioning in the infant (118).

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3. Cross-cultural issues

Culture can influence the experience and communication of symptoms of depression and mania. Underdiagnosis or misdiagnosis, as well as delayed detection of early signs of recurrence, can be reduced by being alert to specific ethnic and cultural differences in reporting complaints of a major mood episode. Specifically, minority patients (particularly African and Hispanic Americans) with bipolar disorder are at greater risk for being misdiagnosed with schizophrenia (119, 120). This greater risk appears to result from clinicians failing to elicit affective symptoms in minority patients with affective psychoses (121).

Ethnicity and race must also be taken into consideration when prescribing medications, since ethnic and racial groups may differ in their metabolism of some medications (122, 123). For example, relative to Caucasian patients, Chinese patients have a lower average activity of the cytochrome P-450 isoenzyme 2D6 (123). As a result, they typically require lower doses of antidepressants and antipsychotics that are metabolized by this enzyme (122). Similar deficits in average activity of the cytochrome P-450 isoenzyme 2C19 have been found in Chinese, Japanese, and Korean patients compared with Caucasians (123).

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4. Children and adolescents

The prevalence of bipolar disorder in a community sample of children and adolescents was 1%; an additional 5.7% had mood symptoms that met criteria for bipolar disorder not otherwise specified (124). Although DSM-IV-TR criteria are used to diagnose bipolar disorder in childhood and adolescence, the clinical features of childhood bipolar disorder differ from bipolar disorder in adults. Children with bipolar disorder often have mixed mania, rapid cycling, and psychosis (125). Child and adolescent bipolar disorder is often comorbid with attention deficit and conduct disorders (126–128). For children and adolescents in a current manic episode, 1-year recovery rates of 37.1% and relapse rates of 38.3% have been reported (1, 129). In a 5-year prospective follow-up of adolescents experiencing bipolar disorder, relapse rates of 44% were found (130). Despite the severity and chronicity of this disorder in children and adolescents and its devastating impact on social, emotional, and academic development, treatment research has lagged far behind that of adult bipolar disorder.

Although there is more information available about the use of lithium and divalproex in children and adolescents with bipolar disorder, other medication treatment options include atypical antipsychotics, carbamazepine, and combinations of these medications.

Treatment with a maintenance agent should continue for a minimum of 18 months after stabilization of a manic episode. There is evidence that ultimate stabilization takes a number of years (131). In addition, lithium discontinuation has been shown to increase relapse rates in adolescents with bipolar disorder: relapse occurred within 18 months in 92% of those who discontinued lithium versus 37% of those who continued lithium (132). Consequently, medication discontinuation should be done gradually at a time when there are no major anticipated stressors.

Psychiatric comorbidity may complicate the diagnosis and treatment of bipolar disorder in children and adolescents. The presence of ADHD, especially in children and adolescents, confounds the assessment of mood changes in patients with bipolar disorder. Early manifestations of mania and hypomania can be particularly difficult to distinguish from the ongoing symptoms of ADHD. Careful tracking of symptoms and behaviors is helpful. In addition, the presence of ADHD is associated with higher rates of learning disabilities, which should be addressed in treatment planning.

Youths with bipolar disorder are at greater risk for substance use disorders (133, 134). Comorbid substance use has been shown to complicate the course of bipolar disorder and its treatment (135). Short-term treatment with lithium (136) and divalproex (137) may be useful in these conditions. However, in a 2-year follow-up of hospitalized manic adolescents, the bipolar disorder patients who continued to abuse substances had more manic episodes and poorer functioning than early-onset bipolar disorder patients who did not exhibit comorbid substance abuse. In contrast, cessation of substance use was associated with fewer episodes and greater functional improvement at the 4-year follow-up point (135).

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5. Geriatric patients

In patients over 65 years of age, prevalence rates of bipolar disorder range from 0.1% to 0.4% (138). In addition, 5%–12% of geriatric psychiatry admissions are for bipolar disorder (138). Relative to patients with onset of mania at a younger age, those with onset at an older age tend to have less of a family history of bipolar disorder. They may also have longer episode durations or more frequent episodes of illness (139). Of individuals with onset of mania at older ages, one-half have had previous depressive episodes, often with a long latency period before the first manic episode (140).

Manic syndromes in geriatric patients may also be associated with general medical conditions, medications used to treat those conditions, or substance use (138–140). The new onset of mania in later life is particularly associated with high rates of medical and neurological diseases (139–141). Right hemispheric cortical or subcortical lesions are especially common. Relative to elderly patients with multiple episodes of mania, geriatric patients with a first episode of mania have a higher risk of mortality (141). Therefore, any patient with a late onset of manic symptoms should be evaluated carefully for general medical and neurological causes (138–140).

General principles for treating geriatric mania are similar to those for younger adults. Older patients will usually require lower doses of medications, since aging is associated with reductions in renal clearance and volume of distribution (142). Concomitant medications and medical conditions may also alter the metabolism or excretion of psychotropic medications (139). Older patients may also be more sensitive to side effects because of greater end-organ sensitivity. Many elderly patients tolerate only low serum levels of lithium (e.g., 0.4–0.6 meq/liter) (138) and can respond to these levels. Those who tolerate low serum lithium levels but who are not showing benefit should have slow dose increases to yield serum levels in the usual therapeutic range.

Older patients may be more likely to develop cognitive impairment with medications such as lithium or benzodiazepines (138). They may also have difficulty tolerating antipsychotic medications and are more likely to develop extrapyramidal side effects and tardive dyskinesia than younger individuals (143). With some antipsychotics and antidepressants, orthostatic hypotension may be particularly problematic and increases the risk of falls. Use of benzodiazepines and of neuroleptics also has been associated with greater risks of falls and hip fractures in geriatric patients (144).

References

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