Recent data indicate that bipolar illness is underdiagnosed and therefore undertreated in the community (Slide 1). A recent survey of >85,000 households in the United States found a 3.7% positive screen for prominent bipolar symptomatology. Using the Mood Disorder Questionnaire, which has good specificity and sensitivity in outpatient clinics, the study also found that the prevalence was higher, 9.3%, among patients 18–24 years of age. However, most disappointing was that only 20% of the positive screens were diagnosed as bipolar, and among those, most were not treated with mood stabilizers. In addition, 31% of patients had been diagnosed with unipolar depression. Several studies have shown that approximately 20% to 40% of presumptively unipolar patients actually have bipolar II or bipolar disorder not otherwise specified. Combined, the data show that bipolar disorder, bipolar depression in particular, is highly prevalent and often misdiagnosed or unrecognized.

Two recent studies found virtually the same data showing that depression is the predominant problem in naturalistically treated bipolar outpatients. Judd and colleagues found that depression was three times more prevalent than mania in bipolar patients. This is exactly what was found in the Stanley Foundation bipolar outpatient follow-up study, which rated the study's first 258 patients every day for 1 year (Slide 2). The study found that patients were ill almost 50% of the time; they were depressed 33% of the days in the year, and hypomanic or manic 10.8% of the days. This occurred despite aggressive treatment with a variety of agents, such as mood stabilizers, antidepressants, and benzodiazepines in 50% of the patients, and typical or atypical neuroleptics in almost 50% of the patients. Thus, even bipolar patients who are intensively treated in academic settings have a very substantial degree of morbidity, particularly depression.

Bipolar depression certainly poses the greatest challenge to clinicians treating bipolar patients. Having a widespread disability associated with it, bipolar depression is often chronic, is less responsive to medication treatment, and has a particularly high rate of suicide. There are currently no drugs approved by the Food and Drug Administration for the treatment of bipolar depression, although full trials have been conducted with lithium, the antipsychotic olan-zapine, and the antiepileptic (AED) lamotrigine. Data for the other AEDs are quite limited and not controlled. The American Psychiatric Association guidelines recommends maximizing the dose in patients who are already on a mood stabilizer and initiating lithium or lamotrigine in patients who are not on a mood stabilizer.

Zornberg and Pope reviewed nine studies comparing lithium to placebo in bipolar depression. Among the 145 patients in these studies, there was detectable response in 79% and an unequivocal response in 36%. Although the studies varied in their methodological design and rigor, they argue quite strongly that lithium is an effective anti-depressant. In addition, six of the seven pre1990 studies evaluating lithium for bipolar depression indicated that the drug had significant antidepressant effects.

The most recent study of lithium for bipolar depression randomly assigned 117 outpatients with acute bipolar depression to treatment with either placebo, Imipramine, or paroxetine. At the 10-week study endpoint, lithium monotherapy was as effective as the addition of an antidepressant, suggesting lithium's antidepressant properties.

Studies have shown that there is some efficacy for a number of agents, most notably lithium, in treating bipolar depression. However, the studies also highlight the unfortunate reality that many patients fail to respond adequately to first-line therapies and that there is a need to identify additional options for patients and clinicians. The atypical antipsychotics clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole, have been the focus of increased interest in the treatment of bipolar depression.

The use of antipsychotics in the treatment of depressive episodes is not a particularly novel idea. In 1982, Robertson and Trimble reviewed 34 studies examining the use of typical antipsychotics to augment an antidepressant and noticed modest but generally consistent benefits. More widespread use of these agents in the management of depression has been limited, however, because of concerns about the long-term risk of tardive dyskinesia and the induction of extrapyramidal symptoms that often mimic depressive symptoms.

Clozapine, the first of the atypicals, was applied initially in the treatment of schizophrenia and schizoaffective disorder, where antidepressant effects were noted during open treatment. Subsequent case series described some benefit in dysphoric manias in bipolar disorder as well.

Much of the inditect evidence for antidepressant effects of the atypicals came from studies in major depressive disorder (MDD). For example, a series of eight patients with MDD who failed treatment with a selective serotonin reuptake inhibitor (SSRI) achieved marked and rapid response when risperidone was added to the SSRI. All patients remitted within 1 week; Hamilton Rating Scale for Depression score in these patients declined from a mean of 20.5 to a mean of 2.4 (Slide 11). A subsequent series of 30 patients yielded similar results.