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

315 Rapid cycling and mixed statesanxiety. None of the cortisol measures correlated with mania or agitation scores.From these data, the authors suggest that increased cortisol secretion is a characteristicof the depressed state in mixed manics, although pure manics may alsohave increased DST non-suppression.Thyroid dysfunction has been implicated by several authors in rapid-cyclingpatients. Sack et al. (1988) reported on decreased nocturnal thyroid-stimulatinghormone (TSH) secretion in rapid-cycling patients. Hypothyroid metabolism hasalso been reported by several authors in rapid cyclers (for a review, see Joffe andSokolov, 1997), and low basal TSH levels also appear to be associated with a higherswitch risk when bipolar depressed patients are exposed to antidepressants(Bottlender et al., 2000). Preliminary clinical data (Bauer and Whybrow, 1990)suggest that thyroxine addition may be a helpful augmentation strategy in refractoryrapid-cycling patients. For mixed patients, however, a correlation to thyroiddysfunction has not been convincingly observed so far. Joffe et al.(1994) found nodifference in the frequency of grade II subclinical hypothyroidsm or thyroidhormone level between mixed (n = 10) and non-mixed (n = 57) manic patients.However, a study of Zarate et al.(1997) in first-episode manic patients, 15 mixedand 57 pure, showed a greater likelihood for elevated TSH in mixed patients, and asmall study of Chang points in the same direction of hypothyroidism in mixedpatients (Chang et al., 1998). In the largest trial looking for thyroid antibodies indifferent mood states in 226 bipolar patients (including 28 patients with mixedstates), Kupka et al.(2002) found no difference in the number of thyroid antibodypositivepatients between euthymic, depressed, and mixed patients.Besides these cited studies, there also several case reports on changes of neuroendocrinologicalabnormalities in rapid-cycling bipolar patients and their ameliorationwith remission (e.g., Shimizu et al., 1997). But all these reports and studiesdo not solve a general problem, and that is causality. Are aberrations of themetabolism of biogenic amines and hormonal changes the cause of mixed statesand rapid cycling or are they simply effects of a different mood state? Or are theyeven completely independent from mood and represent a variable triggered byanother unknown, underlying mechanism which also affects the mood state? Thus,not only the evidence but also the causality of the impact of neurotransmittersand hormones remains weak on the course of mixed state and rapid cycling.The impact of transmembranous ion fluxes on rapid cycling and mixed statesBesides acting on different neurotransmitters (5-hydroxytryptamine, dopamine,gamma-aminobutyric acid, and glutamate: for the latter two no studies haveso far been done for rapid cycling and mixed states), antiepileptic drugs mainlytarget transmembranous ion fluxes. For carbamazepine, valproate, and lamotrigine,