Bipolar Disorders: Mixed States, Rapid-Cycling, and Atypical Forms

373 Investigational strategiesinstance, it is not possible to state with certainty that a patient meeting criteria formania and also having a Hamilton Depression Rating Scale score > 20 meets theDSM criteria for a mixed episode.Most treatment results published for mixed episodes are derived from clinicaltrials conducted primarily to gain regulatory approval for treatment of acutemania. Studies designed for this objective are subject to potentially serious distortionswhen outcomes are reported. In such studies response rates are operationallydefined based on improvement on the mania rating scale without considering thepersistence or worsening of depressive severity. Thus patients with moderatemania at study entry who become severely depressed during the study can meetthe outcome criteria for treatment response. Furthermore, accession bias can havedramatic consequences. At the baseline study visit, clinically depressed bipolarpatients with just one or two moderate manic symptoms, such as irritability,agitation, insomnia, and racing thoughts, may well meet rating scale criteria fora mixed episode. In light of longitudinal data indicating that mixed episodes arevery likely to be chronic (Kupfer et al., 2001), it is surprisingly common to observethat a substantial percentage of subjects in clinical trials with mixed episodes atbaseline meet remission criteria at the week 1 follow-up assessment.Addressing factors related to the specificity of diagnosis and treatment outcomehas great potential to improve the prospects for research on mixed episodes.Standardizing criteria for accession of more uniform samples or at least clearlydefining the condition is a critical need. Himmelhoch et al.(1976) recognized theimportance of secondary factors such as comorbid conditions and psychoactivesubstance use in the phenomenology of mixed episodes. Kraepelin (1921) notedthe occurrence of mixed states and distinguished transient mixed states whichmight arise in the course of cycling from a manic episode to a depression, frompersistent states in which the symptoms of mania and depression co-occurchronically. Entry criteria for studies focusing in mixed states could promotemore homogeneous samples by excluding subjects with known secondary factorsand requiring a duration longer than 4 weeks to improve the homogeneity of theirsample. Studies reporting outcomes for mixed episode should include compositeoutcome measures that employ concurrent assessment of mania and depressionrather than reporting outcome measure related exclusively to mania (e.g., 50%improvement from baseline mania rating scale score).Difficulties in conducting clinical trials for rapid cyclingWhat is rapid cycling? The term ‘‘rapid cycling’’ was coined by Dunner et al.(1977)based on the high frequency of four episodes or more per year among thosepatients with poor response to lithium. Since then, treatment for rapid cycling