III. Special Clinical Features Influencing the Treatment Plan

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A. Psychiatric Features

1. Psychosis

Psychotic symptoms (e.g., delusions, hallucinations) are commonly seen during episodes of either mania or depression but are more common in the former, appearing in over one-half of manic episodes (41). Mood-congruent features during a manic episode probably are not predictive of a poorer outcome, although early onset (before age 21) of psychotic mania may predict a more severe disorder (42). Mood-incongruent features have been identified in some (43) but not all (44) studies to be a predictor of a shorter time in remission. The presence of psychotic features during a manic episode may not require an antipsychotic medication, although most clinicians prescribe them in addition to a maintenance agent (45).

2. Catatonia

Catatonic features may develop in up to one-third of patients during a manic episode (46). The most commonly observed symptoms of catatonia in mania are motor excitement, mutism, and stereotypic movements. Because catatonic symptoms are seen in other psychiatric and neurological disorders, a careful assessment is indicated for an accurate diagnosis. In addition, patients who exhibit catatonic stupor may go on to show more typical signs and symptoms of mania during the same episode of illness (47). The presence of catatonic features during the course of a manic episode is associated with greater episode severity, mixed states, and somewhat poorer short-term outcomes (46). In treating catatonia, neuroleptics have generally exhibited poor efficacy (48). In contrast, prospective studies have demonstrated the efficacy of lorazepam in the treatment of catatonic syndromes, including those associated with mania (49–52). Since ECT is probably the most effective treatment for catatonic syndromes regardless of etiology, ECT should be considered if benzodiazepines do not result in symptom resolution (48).

3. Risk of suicide, homicide, and violence

Like those suffering from major depression, patients with bipolar disorder are at high risk for suicide (53, 54). The frequency of suicide attempts appears similar for the bipolar I and bipolar II subtypes (55, 56). Individuals with bipolar disorder repeatedly have been shown to have greater overall mortality than the general population (41). Although much of this risk reflects the higher rate of suicide, cardiovascular and pulmonary mortality among patients with untreated bipolar disorder is also high (41, 57).

Known general risk factors for suicide also apply to patients with bipolar disorder. These include a history of suicide attempts, suicidal ideation, comorbid substance abuse, comorbid personality disorders (58), agitation, pervasive insomnia, impulsiveness (59), and family history of suicide. Among the phases of bipolar disorder, depression is associated with the highest suicide risk, followed by mixed states and presence of psychotic symptoms, with episodes of mania being least associated with suicide (8, 56). Suicidal ideation during mixed states has been correlated with the severity of depressive symptoms (10). In general, a detailed evaluation of the individual patient is necessary to assess suicide risk (Table 1). Judgment of suicide risk is inherently imperfect; therefore, risks and benefits of intervention should be carefully weighed and documented.

Long-term treatment with lithium has been associated with reduction of suicide risk (56, 60). Whether this reflects an anti-impulsivity factor beyond lithium's mood-stabilizing effect is not yet clear. Lithium may also diminish the greater mortality risk observed among bipolar disorder patients from causes other than suicide (61). It is unknown whether prolonged survival is also seen with the anticonvulsant maintenance agents.

Clinical experience attests to the presence of violent behavior in some patients with bipolar disorder, and violence may be an indication for hospitalization (41). Comorbid substance abuse and psychosis may contribute to the threat of criminal violence or aggression (62–64).

4. Substance use disorders

Bipolar disorder with a comorbid substance use disorder is a very common presentation, with bipolar disorder patients of both sexes showing much higher rates of substance use than the general population (65). For example, the Epidemiologic Catchment Area study found rates of alcohol abuse or dependence in 46% of patients with bipolar disorder compared with 13% for the general population. Comparable drug abuse and dependence figures are 41% and 6%, respectively (66, 67). Substance abuse may obscure or exacerbate endogenous mood swings. Conversely, comorbid substance use disorder may be overlooked in patients with bipolar disorder (68, 69). Substance abuse may also precipitate mood episodes or be used by patients to ameliorate the symptoms of such episodes. Comorbid substance use is typically associated with fewer and slower remissions, greater rates of suicide and suicide attempts, and poorer outcome (70–73).

Treatment for substance abuse and bipolar disorder should proceed concurrently when possible. It is also helpful to obtain consultation from an addiction expert, such as an addiction psychiatrist, or to arrange for concomitant treatment of the bipolar disorder and the substance use disorder in a dual-diagnosis program.

Alcohol abuse and its effects may affect bipolar disorder pharmacotherapy. For instance, alcohol-related dehydration may raise lithium levels to toxicity. Hepatic dysfunction from chronic alcohol abuse or from hepatitis associated with intravenous substance use may alter plasma levels of valproate and carbamazepine (74). If the hepatic dysfunction is severe, the use of these hepatically metabolized medications may be problematic. In these cases, coordination with the patient's primary care physician or gastroenterologist is recommended (75).

5. Comorbid psychiatric conditions

Patients with comorbid personality disorders pose complicated diagnostic pictures. They are clearly at greater risk for experiencing intrapsychic and psychosocial stress that can precipitate or exacerbate mood episodes. Patients with comorbid personality disorders generally have greater symptom burden, lower recovery rates from episodes, and greater functional impairment (76). In addition, these patients may have particular difficulty adhering to long-term treatment regimens (77).

Relative to the general population, individuals with bipolar disorder are at greater risk for comorbid anxiety disorders, especially panic disorder and obsessive-compulsive disorder. Comorbid anxiety disorders may predict a longer time to recovery of mood episodes (78). Treatment for the bipolar disorder and the comorbid anxiety disorder should proceed concurrently.

The presence of comorbid attention-deficit/hyperactivity disorder (ADHD) in adults and children with bipolar disorder may make it difficult to monitor changes in mood states. Of note, adults with bipolar disorder and comorbid ADHD are likely to have experienced a much earlier age at onset of their mood disorder relative to those without comorbid ADHD (79).


B. Demographic and Psychosocial Factors

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).

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).

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.

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).

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).

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.

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).

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).

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).

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).


C. Concurrent General Medical Conditions

In the presence of a severe medical disorder, the disorder itself or the medications used to treat it should always be considered as possible causes of a manic episode. Neurological conditions commonly associated with secondary mania are multiple sclerosis, lesions involving right-side subcortical structures, and lesions of cortical areas with close links to the limbic system (145). l-Dopa and corticosteroids are the most common medications associated with secondary mania (146).

The presence of a general medical condition may also exacerbate the course or severity of bipolar disorder or complicate its treatment (147). For example, the course of bipolar disorder may be exacerbated by any condition that requires intermittent or regular use of steroids (e.g., asthma, inflammatory bowel disease) or that leads to abnormal thyroid functioning. In addition, treatment of patients with bipolar disorder may be complicated by conditions requiring the use of diuretics, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, or salt-restricted diets, all of which affect lithium excretion. Conditions or their treatments that are associated with abnormal cardiac conduction or rhythm or that affect renal or hepatic function may further restrict the choice or dosage of medications. In HIV-infected patients, lower doses of medications are often indicated because of patients' greater sensitivity to side effects and because of the potential for drug-drug interactions. Special considerations in the treatment of HIV-infected patients are presented in the APA Practice Guideline for the Treatment of Patients With HIV/AIDS (148; included in this volume).

Whenever patients are taking more than one medication, the possibility of adverse drug-drug interactions should always be considered. Patients should be educated about the importance of informing their psychiatrist and other physicians about their current medications whenever new medications are prescribed. Clinicians should also inquire about patient use of herbal preparations and over-the-counter medications.


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