The association between course of illness and subsequent morbidity in bipolar I disorder.

OBJECTIVE: We examined the relationship between certain bipolar I disorder clinical course variables over 5 years with outcome over the subsequent 5-year period. METHODS: Prospective observational follow-up data of 123 bipolar I subjects were analyzed. Predictive clinical variables included the frequency and direction of switches, and the quantity, polarity and length of affective periods. Outcome variables were an affective burden index (ABI) accounting for week-by-week severity and weeks hospitalized. Bivariate analyses guided the selection of predictors for multivariable analyses against the outcome variables. RESULTS: Affective burden index: while the number and direction of switches, the number of polyphasic episodes, weeks in hypomania/mania/mixed state, weeks in minor/major depression, weeks in at least marked affective syndrome, and weeks in any affective syndrome all had bivariate correlation (p<0.01) with the ABI, only weeks in hypomania/mania/mixed state and weeks in minor/major depression made significant contributions in the multivariable analysis (p<0.01) with the ABI. Weeks hospitalized: weeks in at least marked affective syndrome were significantly correlated with weeks hospitalized in bivariate analysis (p<0.01), and maintained a contribution to weeks hospitalized in the multivariable analysis (p<0.01). CONCLUSIONS: The quantity and severity of weeks in symptomatic affective states are possibly greater predictors of affective burden in bipolar I patients than the quantity and direction of affective switches.

Coupling of serotonin 5-HT1B receptors to activation of mitogen-activated protein kinase (ERK-2) and p70 S6 kinase signaling systems.

Little is known about the coupling of serotonin 5-HT1B receptors to cellular signals other than cyclic AMP. In the present studies, the activation by 5-HT1B receptors of p70 S6 kinase and the mitogen-activated protein kinase (MAP kinase) ERK-2 was investigated. Studies were performed by using both nontransfected Chinese hamster ovary (CHO) cells, which express endogenous receptors at a very low density, and a stable transfected CHO cell line expressing 5-HT1B receptors at 230 fmol/mg of membrane protein, a density similar to that expressed in cortex. In nontransfected cells, 5-HT was found to stimulate a greater than twofold increase in MAP kinase activity with an EC50 of 20 nM. Reflecting increased density of receptors, 5-HT caused a greater than eightfold activation of ERK-2 in transfected cells with an EC50 of 2 nM. 5-HT was found to also stimulate p70 S6 kinase in both nontransfected and transfected cells. The stimulation was sixfold in both types of cells, but the EC50 for 5-HT was fourfold lower in transfected cells. The coupling of 5-HT1B receptors to ERK-2 and to p70 S6 kinase was inhibited by pertussis toxin, inhibitors of phosphatidylinositol 3-kinase, and by the inhibitor of MAP kinase kinase PD098059. Activation of p70 S6 kinase, but not ERK-2, was also inhibited by rapamycin. These findings demonstrate that 5-HT1B receptors couple to ERK-2 and p70 S6 kinase through overlapping, but nonidentical, pathways.