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

312 H. Grunze and J. WaldenFiève (1974) showing a rapid decline of lithium responsiveness with a cut-off atfour episodes. Recent observations of large patient samples however question this‘‘magic line’’ defined by four episodes. Data from the Stanley Foundation BipolarNetwork (Kupka et al., unpublished data) demonstrate that there is a continuousdecline of treatment response with increasing number of episodes per year. Rapidcycling also includes some rare manifestations which appear to have a highlybiological background, probably coupled to the circadian rhythm and Zeitgeber.However, these patients with 48-rapid cycling only represent a very narrowselection of rapid-cycling patients at large and conclusions from their biologymay be not transferable to rapid-cycling patients with a chaotic and irregularcourse of illness.The reason why it still makes sense to review the biology of rapid cycling andmixed states in one chapter is that some aspects of these manifestations may be incommon. On a theoretical level, mixed states not following this strict definition ofDSM-IV but the wider definition of the Tenth Revision of International Classificationof Diseases (ICD-10: World Health Organization, 1992), which also allows timelyseparation of depressive and manic syndromes, may also be called ultradian rapidcycling. On the level of treatment, evidence from several open and some controlledtrials points towards common principles in drug treatment. It appears to be generalconsensus that lithium is not very effective in both conditions, whereas antiepilepticdrugs, especially valproate and lamotrigine, and also atypical antipsychotics such asolanzapine and risperidone may be more efficacious. To understand aspects of thebiology of rapid cycling and mixed states, another possible approach would thereforebe to look for mechanisms of action of these drugs which are not or onlypartially shared by lithium. We will use this approach in the second part of thischapter.Implications of catecholamines on mixed states and rapid cyclingThe first level to be considered is the cell membrane and the action of differentneurotransmitters that may play a role in affective states. For bipolar disorder ingeneral, results are still conflicting about changes in neurotransmission. Increasedcortical norepinephrine (noradrenaline) and decreased 5-hydroxytryptamine anddopamine turnover has been described in bipolar patients (Manji and Potter, 1997).Within manic patients, the central nervous system levels of norepinephrine appearto increase with the degree of dysphoria, anger, and anxiety (Post et al., 1989). Also acentral serotonergic deficit, in both manic and depressed patients, has been suggested(Meltzer and Lowy, 1987) which may improve after treatment with valproate(Maes et al., 1997). Tandon et al. (1988) compared selected cerebrospinal fluid(CSF) parameters from patients with bipolar disorder, mixed, to those with mania