No abstract

Altered glucocorticoid hormone action may contribute to the etiology of the metabolic syndrome, but the molecular mechanisms are poorly defined. Tissue sensitivity to glucocorticoid is regulated by expression of the glucocorticoid receptor (GR)-␣ and 11␤-hydroxysteroid dehydrogenase type I (11␤-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GR␣ and 11␤-HSD1 expression in skeletal myoblasts from men (n ‫؍‬ 14) with contrasting levels of insulin sensitivity (euglycemic clamp measurements of insulin-dependent glucose disposal rate), blood pressure, and adiposity. Positive associations were evident between myoblast expression of GR␣ under basal conditions and levels of insulin resistance (r 2 ‫؍‬ 0.34, P < 0.05), BMI (r 2 ‫؍‬ 0.49, P < 0.01), percent body fat (r 2 ‫؍‬ 0.34, P < 0.02), and blood pressure (r 2 ‫؍‬ 0.86, P < 0.001). Similar associations were evident when myoblasts were incubated with physiological levels of cortisol (P < 0.01 for all). Importantly, GR␣ expression was unaffected by variations in in vivo concentrations of insulin, IGF-1, or glucose concentrations. In common with the GR, 11␤-HSD1 expression in myoblasts incubated with physiological concentrations of cortisol in vitro was positively associated with levels of insulin resistance (r 2 ‫؍‬ 0.68, P < 0.001), BMI (r 2 ‫؍‬ 0.63, P < 0.005), and blood pressure (r 2 ‫؍‬ 0.27, P < 0.05). Regulation of GR␣ and 11␤-HSD1 by cortisol was abolished by the GR antagonist RU38486. In summary, our data suggest that raised skeletal muscle cell expression of GR␣ and 11␤-HSD1-mediated regulation of intracellular cortisol may play a fundamental role in mechanisms contributing to the pathogenesis of the metabolic syndrome.

This preliminary study replicates open-label findings showing that divalproex is an efficacious treatment for explosive temper and mood lability in disruptive children and adolescents.

Background:The literature is inconclusive on the role of antidepressant medications in treating drug dependence. Studies have either not focused on depressed patients or have selected patients with depressive disorders based on cross-sectional symptoms rather than a syndromal diagnosis. A clinical trial of an antidepressant was, therefore, conducted on drug-dependent patients with syndromal depression.

There is a noticeable lack of targeted treatment options for marijuana dependence, in particular pharmacologic approaches. This is the first study evaluating a targeted pharmacologic approach for marijuana dependence. The goals of the study were to determine if such patients would seek pharmacologic treatment, whether these patients could be retained in treatment using a design previously developed for cocaine-dependent patients, and especially whether divalproex sodium showed promise as a treatment agent for marijuana dependence. We found that marijuana-dependent patients will seek treatment, and such patients can be adequately maintained in a pharmacologic trial. Regardless of treatment group, patients reported a significant reduction in their frequency and amount of marijuana use as well as a reduction in irritability. Given the lack of proven effective treatments for marijuana dependence, pharmacotherapies should be sought. The design of a preliminary clinical trial should include a psychosocial/behavioral intervention emphasizing motivation and medication compliance and a placebo control group.