A group of mood-stabilizing drugs that are also anticonvulsant agents has become more widely used than lithium. It includes carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by the FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by the FDA for treatment of the manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for treatment of bipolar depression.
Nature of Bipolar Affective Disorder
Bipolar affective disorder occurs in 1–3% of the adult population. It may begin in childhood, but most cases are first diagnosed in the third and fourth decades of life. The key symptoms of bipolar disorder in the manic phase are expansive or irritable mood, hyperactivity, impulsivity, disinhibition, diminished need for sleep, racing thoughts, psychotic symptoms in some (but not all) patients, and cognitive impairment. Depression in bipolar patients is phenomenologically similar to that of major depression, with the key features being depressed mood, diurnal variation, sleep disturbance, anxiety, and sometimes, psychotic symptoms. Mixed manic and depressive symptoms are also seen. Patients with bipolar disorder are at high risk for suicide.
The sequence, number, and intensity of manic and depressive episodes are highly variable. The cause of the mood swings characteristic of bipolar affective disorder is unknown, although a preponderance of catecholamine-related activity may be present. Drugs that increase this activity tend to exacerbate mania, whereas those that reduce activity of dopamine or norepinephrine relieve mania. Acetylcholine or glutamate may also be involved. The nature of the abrupt switch from mania to depression experienced by some patients is uncertain. Bipolar disorder has a strong familial component, and there is abundant evidence that bipolar disorder is genetically determined.
Many of the genes that increase vulnerability to bipolar disorder are common to schizophrenia but some genes appear to be unique to each disorder. Genome-wide association studies of psychotic bipolar disorder have shown replicated linkage to chromosomes 8p and 13q. Several candidate genes have shown association with bipolar disorder with psychotic features and with schizophrenia. These include genes for dysbindin, DAOA/G30, disrupted-in-schizophrenia-1 (DISC-1), and neuregulin 1.
Lithium was first used therapeutically in the mid-19th century in patients with gout. It was briefly used as a substitute for sodium chloride in hypertensive patients in the 1940s but was banned after it proved too toxic for use without monitoring. In 1949, Cade discovered that lithium was an effective treatment for bipolar disorder, engendering a series of controlled trials that confirmed its efficacy as monotherapy for the manic phase of bipolar disorder.
Lithium is a small monovalent cation. Its pharmacokinetics are summarized in Table 29–5.
Despite considerable investigation, the biochemical basis for mood stabilizer therapies including lithium and anticonvulsant
TABLE 29–5 Pharmacokinetics of lithium.