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

316 H. Grunze and J. Waldenblockade of fast sodium inward currents may be a decisive mechanism of antiepilepticaction. For bipolar disorder in general, calcium (and probably potassium)fluxes may be the more important target.A potential role of calcium in bipolar disorder?Mobilization of calcium is a key event in presynaptic and postsynaptic signallingand also in lasting neuronal changes, as long-term potentiation.Increased intracellular calcium concentrations, under baseline conditions or aftermobilization following specific stimulation paradigms, are a solid finding in plateletsand lymphocytes of bipolar patients, in both manic and depressive episodes (cf.Grunze et al., 1997;Houghet al., 1999). If we allow the speculative assumption thatthese findings in peripheral cells also reflect the neuronal environment, we suggestthe following simplified model: mild elevations of intracellular calcium activatemetabolic processes, by activating adenylate cyclase. This increases, beside othercyclic adenosine monophosphate-activated protein kinase-dependent steps, thesynthesis of catecholamines by phosphorylation of tyrosine hydroxylase, leading toincreased neuronal excitability. Excitability may also be increased by a partialinhibition of the Na, K-ATPase activity (el Mallakh and Wyatt, 1995). The clinicalcounterpart may be a manic syndrome. Further increase of intracellular calcium,however, dampens the adenylate cyclase activity even below its normal level,decreasing catecholamine synthesis, and, hypothetically, may lead to a state of lastingneuronal depolarization by maximum inhibition of Na, K-ATPase. This state maymanifest itself clinically as depression. If patients are now recovering from depression,the intracellular calcium declines on its way to normalization, passing a levelthat may again activate adenylate cyclase, causing the often-observed hypomanicstate after depression. Calcium concentrations fluctuating around the thresholdbetween the manic and depressed stage may be a hypothetical origin of mixed statesor ultradian cycling.In conclusion, this hypothesis combines special potential factors of vulnerabilityin bipolar patients, such as altered Na, K-ATPase (Antia et al., 1995) and adenylatecyclase activity (Meltzer, 1986), with the potentiating effects of increased intracellularcalcium mobilization or calcium influx into the cell.How do antiepileptic drugs used in treating mixed states and rapid cyclingpotentially interfere with intracellular calcium signalling?A well-known target of lithium action is the inositol phospholipid pathwaywhich shows increased sensitivity in bipolar patients (Moscovich et al., 1990).Inositol 1, 4, 5-triphosphate (IP 3 ) synthesis mobilizes intracellular calcium stores