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

313 Rapid cycling and mixed statesand major depression. Fourteen patients in each category (DSM-III) were studiedwith regard to the dopamine metabolite homovanillic acid (HVA) and the serotonergicmetabolite 5-hydroxyindoleacetic acid (5HIAA) in CSF under carefullycontrolled conditions. Both CSF HVA and 5HIAA were found to be significantlyhigher in manic than in major depressive patients. Discriminant analysis of thebiochemical variables of the mixed affective group identified two biochemicallydistinct and clinically different subgroups of seven patients each, one resemblingthe manic group and the other the major depressive group. Tandon et al.concludefrom these findings that mixed affective states do not exist as a separate entity,but are composed of two subgroups obtained from the manic and major depressivecategories – a view that remains controversial (McElroy et al., 2000).However, other studies make a strong monoaminergic link to mixed states lesslikely, as they reported no change in either 5-HT2A or 1A receptor density (Deanet al., 2001) and, as far as the noradrenergic action is concerned, no change in betareceptordensity (Werstiuk et al., 1990).As bipolar illness is quite heterogeneous, more precise results may be expectedin a homologous group of patients. Therefore, several studies looked at a monoaminergicimbalance in 48-h rapid-cycling patients.Characteristic and reproducible changes in norepinephrine and metanephrineexcretion, closely related to mood swings, were described by Juckel et al. (2000). Ingeneral, the urinary excretion of norepinephrine and metanephrine was increased onboth manic and depressed days, with higher values during mania, and was generallyameliorated after successful valproate treatment. As far as mixed states are concerned,Swann et al.(1994) reported on increased 3-methoxy-4-hydroxyphenylethyleneglycolexcretion in mixed states. As especially tricyclic noradrenergic acting antidepressantsare capable of inducing a switch from pure depression into mixed states or mania, andmay also induce a rapid-cycling course, norepinephrine and its metabolites may playat least a strongly modulating role in these conditions.Concerning an impact of the serotonergic system, a very high and, compared tobipolar disorder in general, increased comorbidity has been described betweenmixed states, obsessive-compulsive disorder, and anxiety disorders, which aregenerally considered as serotonergic disorders. Thus, for mixed states the serotonergicsystem may also play a role. From clinical observation, this appears lesslikely for rapid cycling, as selective serotonin reuptake inhibitors are considered agenerally safe treatment for possible induction of switch or rapid cycling.To our knowledge, mixed states and rapid cycling have not yet been explored witha special focus on the dopaminergic system, with the exception of the cited study ofTandon et al.(1988). In general, a dopamine hypothesis of mania has been proposedby several authors (Diehl and Gershon, 1992; Buki and Goodnick, 1998) and geneticaberrations of dopamine receptors and transporters have been demonstrated in