Clinical Manifestations

Bipolar disorder is characterized by unpredictable swings in mood from mania (or hypomania) to depression. Some patients suffer only from recurrent attacks of mania, which in its pure form is associated with increased psychomotor activity; excessive social extroversion; decreased need for sleep; impulsivity and impairment in judgment; and expansive, grandiose, and sometimes irritable mood (Table 371-10). In severe mania, patients may experience delusions and paranoid thinking indistinguishable from schizophrenia. Half of patients with bipolar disorder present with a mixture of psychomotor agitation and activation with dysphoria, anxiety, and irritability. It may be difficult to distinguish mixed mania from agitated depression. In some bipolar patients (bipolar II disorder), the full criteria for mania are lacking, and the requisite recurrent depressions are separated by periods of mild activation and increased energy (hypomania).

In cyclothymic disorder, there are numerous hypomanic periods, usually of relatively short duration, alternating with clusters of depressive symptoms that fail, either in severity or duration, to meet the criteria of major depression. The mood fluctuations are chronic and should be present for at least 2 years before the diagnosis is made.

Manic episodes typically emerge over a period of days to weeks, but onset within hours is possible, usually in the early morning hours. An untreated episode of either depression or mania can be as short as several weeks or last as long as 8 to 12 months, and rare patients have an unremitting chronic course. The term rapid cycling is used for patients who have four or more episodes of either depression or mania in a given year. This pattern occurs in 15% of all patients, almost all of whom are women. In some cases, rapid cycling is linked to an underlying thyroid dysfunction and, in others, it is iatrogenically triggered by prolonged antidepressant treatment. Approximately half of patients have sustained difficulties in work performance and psychosocial functioning.

Bipolar disorder is common, affecting 1% of the population in the United States. Onset is typically between 20 and 30 years of age, but many individuals report premorbid symptoms in late childhood or early adolescence. The prevalence is similar for men and women; women are likely to have more depressive and men more manic episodes over a lifetime.

Differential Diagnosis
The differential diagnosis of mania includes toxic effects of stimulant or sympathomimetic drugs as well as secondary mania induced by hyperthyroidism, AIDS, or neurologic disorders, such as Huntington’s or Wilson’s disease, or cerebrovascular accidents. Comorbidity with alcohol and substance abuse is common, either because of poor judgment and increased impulsivity or because of an attempt to self-treat the underlying mood symptoms and sleep disturbances.

Etiology and Pathophysiology
Evidence for a genetic predisposition to bipolar disorder is significant. The concordance rate for monozygotic twin pairs approaches 80%, and segregation analyses are consistent with autosomal dominant transmission. Multiple genes are likely to be involved, with strongest evidence for loci on chromosomes 18p, 18q, 4p, 4q, 5q, 8p, and 21q.

The pathophysiologic mechanisms underlying the profound and recurrent mood swings of bipolar disorder remain unknown. Neuroimaging studies have documented alterations in amygdala volume as well as increases in white matter hyperintensities. Cellular models of changes in membrane Na+- and K+ -activated ATPase and proposals of disordered signal transduction mechanisms involving the phosphoinositol system and GTP-binding proteins have received the most attention. Neurophysiologic studies suggest that patients with bipolar disorder have altered circadian rhythmicity. Lithium may exert its therapeutic benefit through a resynchronization of intrinsic rhythms keyed to the light/dark cycle.

Treatment
Table 371-11. Lithium carbonate is the mainstay of treatment in bipolar disorder, although sodium valproate and olanzapine are equally effective in acute mania, as is lamotrigine in the depressed phase. The response rate to lithium carbonate is 70 to 80% in acute mania, with beneficial effects appearing in 1 to 2 weeks. Lithium also has a prophylactic effect in prevention of recurrent mania and, to a lesser extent, in the prevention of recurrent depression. A simple cation, lithium is rapidly absorbed from the gastrointestinal tract and remains unbound to plasma or tissue proteins. Some 95% of a given dose is excreted unchanged through the kidneys within 24 h.

Serious side effects from lithium administration are rare, but minor complaints such as gastrointestinal discomfort, nausea, diarrhea, polyuria, weight gain, skin eruptions, alopecia, and edema are common. Over time, urine-concentrating ability may be decreased, but significant nephrotoxicity does not usually occur. Lithium exerts an antithyroid effect by interfering with the synthesis and release of thyroid hormones. More serious side effects include tremor, poor concentration and memory, ataxia, dysarthria, and incoordination. There is suggestive, but not conclusive, evidence that lithium is teratogenic, inducing cardiac malformations in the first trimester.

In the treatment of acute mania, lithium is initiated at 300 mg bid or tid, and the dose is then increased by 300 mg every 2 to 3 days to achieve blood levels of 0.8 to 1.2 meq/L. Because the therapeutic effect of lithium may not appear until after 7 to 10 days of treatment, adjunctive usage of lorazepam (1 to 2 mg every 4 h) or clonazepam (0.5 to 1 mg every 4 h) may be beneficial to control agitation. Antipsychotics are indicated in patients with severe agitation who respond only partially to benzodiazepines. Patients using lithium should be monitored closely, since the blood levels required to achieve a therapeutic benefit are close to those associated with toxicity.

Valproic acid is an alternative in patients who cannot tolerate lithium or respond poorly to it. Valproic acid may be better than lithium for patients who experience rapid cycling (i.e., more than four episodes a year) or who present with a mixed or dysphoric mania. Tremor and weight gain are the most common side effects; hepatotoxicity and pancreatitis are rare toxicities.

Carbamazepine and oxcarbazepine, although not formally approved by the U.S. Food and Drug Administration (FDA) for bipolar disorder, have clinical efficacy in the treatment of acute mania. Preliminary evidence also suggests that other anticonvulsant agents such as levtiracetam, zonisamide, and topiramate may possess some therapeutic benefit.

The recurrent nature of bipolar mood disorder necessitates maintenance treatment. A sustained blood lithium level of at least 0.8 mEq/L is important for optimal prophylaxis and has been shown to reduce risk of suicide, a finding not yet apparent for other mood stabilizers. Compliance is frequently an issue and often requires enlistment and education of concerned family members. Efforts to identify and modify psychosocial factors that may trigger episodes are important, as is an emphasis on lifestyle regularity. Antidepressant medications are sometimes required for the treatment of severe breakthrough depressions, but their use should generally be avoided during maintenance treatment because of the risk of precipitating mania or accelerating the cycle frequency. Loss of efficacy over time may be observed with any of the mood-stabilizing agents. In such situations, an alternative agent or combination therapy is usually helpful.

Consensus guidelines for the treatment of acute mania and bipolar depression are described in Table 371-12.