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

267 Comorbidity in mixed states and rapid-cycling disordersdisorder may have more illness episodes than patients with bipolar affective disorderwithout substance-abuse disorder (Sonne and Brady, 1999; Calabrese et al., 2000),but not all data support such a hypothesis. Yet, patients with substance abuse andbipolar affective disorders differ from patients with bipolar affective disorders withoutsubstance abuse in other respects: they show more hospitalization (Brady et al., 1991),have an earlier age at onset of bipolar disorder (Sonne et al., 1994; Brieger et al., inpreparation) and have an overall more unfavorable course of bipolar illness (Sonneand Brady, 1999; Marneros and Brieger, 2002; Brieger et al., in preparation).Anxiety disordersThere is a fundamental relationship between bipolar affective disorder and anxietydisorders (including obsessive-compulsive disorder: OCD) (Perugi et al., 1999;Zarate and Tohen, 1999; Brieger, 2000), which has been shown by epidemiological(e.g., Kessler, 1999) and clinical (e.g., McElroy et al., 2001; Perugi et al., 2001)studies. Panic disorder, social phobia, and OCD seem to have a specific relationshipwith bipolar affective disorder (Chen and Dilsaver, 1995a, b; Perugi et al., 1999).One series of factor analyses (Cassidy et al., 1998a, b, 2001a, 2001b) delineatedfive independent factors in mania: (1) dysphoric mood; (2) psychomotor pressure;(3) psychosis; (4) increased hedonic function; and (5) irritable aggression. Thefactor ‘dysphoria’ strongly correlated with anxiety. Based on these studies, analternative set of six diagnostic criteria for mixed episodes was proposed (Cassidyet al., 2000), which (with a threshold of two symptoms) consisted of (1) anxiety;(2) depressed mood; (3) anhedonia; (4) guilt; (5) suicide; and (6) fatigue. In thisconcept, anxiety is an integral aspect of mixed bipolar affective phenomenology, aswas earlier observed by Post et al. (1989). Furthermore, a comparison betweenpatients with mixed mania and agitated depression (Swann et al., 1993)provedthatthese two groups were (at least partially) similar in respect to observed anxiety.These observations support the idea that dysphoria and bipolar mixed states arecharacterized by elevated levels of dimensional anxiety. This is in agreement withthe theories of Akiskal, Koukopoulos, and others, who have postulated that mixedbipolar affective disorders are the product of an admixture of anxiety or depressivesymptoms (or such temperaments) with manic episodes (Koukopoulos andKoukopoulos, 1999; Akiskal and Pinto, 2000; Akiskal et al., 2002). In a comparisonof bipolar patients with pure and mixed manic episodes, we found that patientswith mixed mania exhibited higher rates of anxious temperament than patientswith pure mania (Brieger et al., 2003b). Here, anxious temperament may beinterpreted as a trait marker with longitudinal stability. Nevertheless, there arestudies that do not support such an idea and have found no significant differencebetween patients with mixed and pure manic episodes concerning dimensional