Perspective for new pharmacological interventions

Assessment of current status of therapeutics The range of treatments approved for bipolar disorder (BD) has changed little over the past decade. Studies of mania have had several advantages over studies of depression or other behavioral facets of BDs. A straightforward paradigm of studying a drug versus placebo in hospitalized manic patients and employment of change in a short, 10-item scale has proved a robust model for all currently approved drugs (Williams et al., 1992; Tohen et al., 2003). Enrollment into such studies has been relatively easy to achieve, as hospitalization is clinically indicated for most such patients, patients are readily assessed while in inpatient setting, and side effects are relatively well tolerated for a short period by manic patients. Fewer studies and fewer treatments are available for depression in BD. Complexities include difficulties in establishing prior manic or hypomanic episodes when cross-sectionally evaluating patients while depressed, higher rates of response on placebo in depression trials, and limited evidence regarding whether depression in bipolar I and II patients can be equated (Calabrese et al., 2000; Bowden, 2001; Kessler et al., 2005). Studies of new molecules have been limited in part by traditional rating scales, which, though adequately sensitive to identify overall reduction from syndromal levels of severity, do not have a sufficient range of items covering the spectrum of bipolar symptoms to provide the component analyses needed to establish the areas of behavior that might be specific to one drug, or a particular combination regimen. A treatment that might benefit a particular component of bipolar symptomatology, e.g., anxiety or irritability, is unlikely to be tested with adequate sensitivity with traditional scales. This limitation of both scales and current clinical trial study paradigms has become more evident, with data consistently indicating higher comorbidity of BD with other axis 1 disorders than any other axis 1 conditions, and studies that establish a relatively consistent group of dimensions, or domains of disturbed behavior in BDs (Table 19.1) (Altman et al., 1994; Cassidy et al., 1998; Hollander et al., 2001, 2003; Swann et al., 2001, 2002). Evidence indicates that there is relatively selective efficacy of some mood stabilizers on components of bipolar conditions, rather than across-the-board efficacy.