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

341 The treatment of bipolar mixed stateson antidepressants, of which 35% were antidepressant-induced. However, in arandomized, double-blind, prospective trial (Altshuler et al., 2003), the risk ofdepressive relapse was significantly lower in patients continuing the antidepressantscompared to those discontinuing after remission, with no statistically significantdifference for breakthrough manic episodes. Generally, clinical practicefavors protecting the bipolar patient from manic switches and cycle acceleration bythe preferred use of mood stabilizers over antidepressants, or their combination.This approach is not necessarily supported by the literature, but a recent reviewconcluded that patients taking an antidepressant without a mood stabilizer aremore likely to develop a manic or hypomanic episode than patients who are alsotaking a mood stabilizer (Ghaemi and Goodwin, 1999).Resistance to treatment in mixed statesIt has been thought that mixed states are less responsive to treatment than pure orclassical manic states. Himmelhoch et al. (1976) identified mixed states in 26/84(31%) of manics in 143 consecutive admissions in Yale and Pittsburgh. Alcoholand sedative misuse was more common in the mixed patients. Poor prognosis(strongly influenced by poor response to lithium) was more common in mixedpatients, and this was only partially accounted for by the association with substancemisuse. Paradoxically, 10/14 mixed patients with psychotic features showeda good response to lithium, whereas only 1/12 mixed patients without psychoticfeatures did so. A total of 47/58 with pure mania responded well to treatment.This suggested to Himmelhoch and Garfinkel (1986) that the non-psychoticmixed patients had some other poor prognostic factor and, in a second series of46 lithium-resistant bipolar patients, they identified a substantial frequency offeatures of organic brain disease (developmental disorders, and electroencephalographicabnormalities). In all, 37/46 of these patients had mixed states and 31 ofthese 37 had these neuropsychiatric factors (Himmelhoch and Garfinkel, 1986).However, 23 out of the group of 46 were in adolescence, suggesting that factorsinvolved in the selection process may have produced a somewhat unrepresentativesample. In the combined groups of 63 mixed manic presentations, only 1/45with additional neuropsychiatric or substance misuse factors responded tolithium–antidepressant combinations; by contrast, 10/18 with uncomplicatedmixed mania responded to this combination. Only 11 of the 45 showed psychoticfeatures. Perugi et al. (1997) found that mixed states took longer to recover.Keller et al. (1986) also found mixed manic patients less responsive to lithiumthan other manic patients. Secunda et al. (1987b) found a good response tolithium in 10/11 patients with pure mania (91%) but in significantly fewer (2/7)who had mixed mania (29%). Himmelhoch and Garfinkel (1986) reported that