1998]. Wolkowitz and colleagues also reported the antidepressant effect of ketoconazole as monotherapy in 10 patients with hypercortisolaemic depression but not in those with normal cortisol levels. There has been one open-label trial and one placebo-controlled

double-blind study of augmentation of serotonergic antidepressants with metyrapone. Rogoz and colleagues reported an open-label trial of augmentation of imipramine with Inhibitors,research,lifescience,medical metyrapone in patients with TRD. Patients commenced imipramine treatment for 6 weeks, followed by 6 weeks of the addition of metyrapone (250 mg twice daily) treatment [Rogoz et al. 2004]. Metyrapone augmentation significantly reduced the scores on the depression rating scales [HDRS (46%) and Beck Depression Inventory (39%)]. It was also found that metyrapone’s action was not related to an increase in plasma imipramine concentrations as the latter were unchanged. However, the most robust evidence for the use of metyrapone in depression comes from a placebo-controlled double-blind randomized trial by Jahn and colleagues [Jahn et al. 2004]. Sixty-three Inhibitors,research,lifescience,medical inpatients with depression received augmentation

of nefazodone or fluvoxamine Inhibitors,research,lifescience,medical for 3 weeks with placebo or 1 g of metyrapone once daily. The group treated with metyrapone showed a significantly greater improvement compared with the placebo group (effect size of 0.6) using response (a decrease in HDRS score by 50%, 5 weeks post initiation of treatment) as the outcome measure. Unlike some of the previous studies [Murphy et al. 1991; O’Dwyer et al. 1995] described

above, Jahn used a standard dose of metyrapone (rather than adjusting the dose according to cortisol levels). Inhibitors,research,lifescience,medical The change in morning plasma cortisol levels during metyrapone treatment did not reach statistical http://www.selleckchem.com/products/YM155.html significance. Patients who showed an improvement in their HDRS score with metyrapone augmentation appeared to have higher levels of ACTH and 11-deoxycortisol compared with those whose condition did not respond, though the difference did not reach statistical significance. Thus there is positive evidence for the use of metyrapone Inhibitors,research,lifescience,medical for the treatment of depression. However the exact mechanism of the antidepressant effect of metyrapone Mannose-binding protein-associated serine protease is not clear. Possible mechanisms include GR upregulation, alteration of the sensitivity of 5HT1A in the forebrain, activation of the MR or an antidepressant effect induced by other hormones in the steroid pathway. The absence of a significant reduction of cortisol in the Jahn study and the failure of another study [Raven et al. 1996] to show a correlation between response and cortisol levels argues against a simple reduction in plasma cortisol being the mechanism of action. However, these findings do not exclude the possibility that more subtle changes in cortisol dynamics caused by metyrapone (for instance a reduction in the trough levels) may underlie the therapeutic effect.