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

318 H. Grunze and J. Waldentogether with other controlled evidence (Calabrese et al., 1999), this may suggest thatits main benefit comes from treating and preventing depressive symptoms.A recent review (Grunze et al., 2002b) also highlighted effects of mood stabilizerson potassium channels. Unfortunately, aberrations of potassium currents orgenes coding for potassium channels have not been explored so far with a specialfocus on mixed states and rapid cycling. But again, as valproate as well aslamotrigine and carbamazepine seems to act on potassium channels (which isnot described for lithium), a key function of potassium channels in atypicalmanifestations of bipolar disorder can be hypothesized. Nevertheless, proof forthis is still needed in both basic and clinical research.Other mechanisms of mood stabilizers possibly related to rapid cyclingand mixed statesThe effects of antiepileptic drugs that are efficacious in mixed states and rapidcycling also include a variety of intracellular action targeting the protein kinaseactivity, the inositol phosphate metabolism, and finally the expression of earlygenes and cytoprotective proteins. These issues have also been reviewed extensivelyin a recent publication of the authors (Grunze et al., 2002b). More thanany transient effects on the cell surface, they may supply a key to remission andsuccessful long-term prophylactic treatment with mood stabilizers in bipolardisorder. Data for valproate and lithium showing these effects are available, butare not yet available for the newer anticonvulsants or atypical antipsychotics.However, these data originate from the lab bench and are not reproduced evenin animal models, not to mention rapid-cycling or mixed patients. Thus, relatingany of these interesting activities of the drug to mixed states and rapid cycling ispurely speculative. Additionally, as far as we know, lithium is at least as effectiveas valproate on this intracellular level. Thus, we may not find any specificityfor influencing a rapid-cycling course or mixed state on this level.Again speculative, but only little attention has so far been given to the effect ofchanges of the intracellular proton equilibrium (pH) in bipolar patients. Alreadyvery moderate changes in intracellular pH have a strong effect on both receptorsensitivity and second messenger systems. Even small fluctuations may have astrong impact on the expression of mood. Thus, looking for an easy trigger of rapidcycling and mixed states, changes in intracellular pH may qualify. As a matter offact, a decrease in intracellular pH in the frontal lobe has been described in drugfreebipolar patients (Kato et al., 1998), suggesting aberrations of the protonequilibrium in bipolar disorder. Controlled studies with magnetic resonancespectroscopy in mixed and rapid-cycling patients and correlation with moodstates are therefore, in our opinion, urgently required.