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

314 H. Grunze and J. Waldenbipolar patients (Kelsoe et al., 1996; Mankiet al., 1996; Waldmanet al., 1997).Recently, the D 2 -receptor region came out as a candidate locus associated specificallywith bipolar disorder (Massat et al., 2002). Decreased presynaptic dopaminefunction in the basal ganglia after successful treatment of mania with valproatehas been demonstrated in a recent positron emission tomography study (Yathamet al., 2001). However, so far no study on the dopaminergic system seems to have aspecial focus on rapid cycling.Taken together, data on aberrations of biogenic amines in rapid cycling andmixed states are sparse, with the best evidence so far existing for distinct abnormalitiesof the noradrenergic metabolism, at least in 48-h ultrarapid-cycling patients.Generalizing these results to rapid cycling at large and mixed states, however,would be premature.Implications of hormonal aberrations on mixed states and rapid cyclingThecasereportofJuckelet al.(2000) not only looked into biogenic amines, but alsointo changes of the limbic–hypothalamic–pituitary–adrenocortical axis in this 48-hrapid-cycling patient. Changes of both human growth hormone and cortisol werequite dramatic, with peaks during mania and troughs during depression. Again,successful valproate treatment ameliorated this rollercoaster of the LHPA axis.As far as mixed states are concerned, a small study of Cassidy et al. (1998)compared seven mixed patients with purely manic patients concerning theirplasma dexamethasone concentration and cortisol response in the dexamethasonesuppression test (DST) during manic episodes. Measuring these parameters at 3and 10 p.m., there was a tendency to decreased dexamethasone and increasedcortisol levels in the mixed group. Other studies, unfortunately not exceeding 10patients, reconfirm a tendency for increased DST non-suppression (Evans andNemeroff, 1983; Krishnan et al., 1983).Swann et al. (1992) investigated HPA function and its relationship to clinicalstate in 19 hospitalized manic patients meeting Schedule for Affective Disordersand Schizophrenia – Research Diagnostic Criteria for acute manic episodes,compared patients with and without a mixed presentation, and examined thecorrelation between HPA activity and behavior. In this study, data were availablefrom 13–16 patients. Patients with mania had elevated CSF and urinary freecortisol excretion compared with healthy subjects, and did not differ fromdepressed patients in any cortisol measures. Mixed manic patients had significantlyhigher morning plasma cortisol, postdexamethasone plasma cortisol andCSF cortisol than pure manics. Five of seven mixed manics and three of nine puremanics were DST non-suppressors. Afternoon plasma cortisol and CSF cortisolcorrelated significantly with depressed mood; urinary free cortisol correlated with