ABSTRACT
BACKGROUND: Optimising treatments for patients with treatment-resistant depression (TRD) is key to reducing the burden of this severe illness. The anti-glucocorticoid medication metyrapone has mixed evidence supporting a role as a possible augmentation treatment in TRD. The degree of treatment resistance in depression has been associated prospectively and retrospectively with elevated inflammation, and inflammatory activity may influence responses to antidepressant treatments. AIMS: To investigate whether levels of pro-inflammatory cytokines are associated with clinical outcomes to metyrapone or placebo. METHODS: A double-blind RCT randomised patients with TRD to 3 weeks of placebo or metyrapone augmentation to ongoing serotonergic antidepressants. No benefit of metyrapone was reported in the primary analysis. The current study assessed levels of pro-inflammatory proteins interleukin-6 (IL-6), tumour necrosis factor (TNFα), c-reactive protein (CRP) and interleukin-10 (IL-10) before randomisation and after treatment as potential moderators and/or mediators of clinical outcomes. RESULTS: The three pro-inflammatory proteins (but not IL-10) were elevated in this sample of patients with TRD compared to a non-affected control group. High pre-treatment IL-6 levels predicted a poorer response in the trial overall but did not moderate response to metyrapone versus placebo. Changes in IL-6 indirectly mediated depression outcome, with metyrapone increasing IL-6 levels and IL-6 increase associated with a poorer outcome on depression. Other inflammatory proteins did not mediate or moderate treatment outcomes. INTERPRETATION: Metyrapone is hypothesised to have a therapeutic effect in depression on the basis of inhibiting the synthesis of cortisol. In this study, metyrapone did not reduce cortisol, possibly due to glucocorticoid system overcompensation). The mediation effect of IL-6 may support this and perhaps help to indicate why the treatment was not effective.
ABSTRACT
Depression affects a significant proportion of the population, with 1-year and lifetime prevalence of 3-5% and 10-30% respectively. Full remission is achieved in only a third of patients following treatment with first-line antidepressant. There is a need for novel treatments for treatment-resistant depression (TRD). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been described in patients with depression. There is persistent rise in the levels of cortisol (end product of the HPA axis) and impairment of the negative feedback inhibition mechanism of the HPA axis. Dysregulation of the HPA axis has been found to be linked to nonresponse to antidepressants and relapse following successful treatment. The efficacy of pharmacological agents that intervene with the mechanisms involved in dysregulation of cortisol synthesis and release are being explored in depression, particularly in TRD. Studies have been carried out with these drugs as augmenting agents for antidepressants or as monotherapy. The strongest evidence has come from studies using metyrapone, a cortisol synthesis inhibitor, and this has been described in detail in this review. The most robust evidence for its antidepressant efficacy in depression comes from a double-blind, randomized, placebo-controlled study of augmentation of serotonergic antidepressants with metyrapone. A 3-week augmentation of serotonergic antidepressants with 1 g metyrapone daily was shown to be superior to placebo in reducing the Montgomery-Asberg Depression Rating Scale by 50%, 5 weeks following initiation of treatment. The mechanism of the antidepressant action of metyrapone is not clear but the evidence for various potential mechanisms is discussed.
ABSTRACT
BACKGROUND: Sodium valproate is an anticonvulsant that is also one of the common treatments used for bipolar disorder. The present study was conducted in psychiatric patients with the aim of examining the effects of valproate on hematological parameters and to explore any association with sex and age. METHODS: A list of all psychiatric patients who underwent valproate level estimation in the years 2004-2008 in Newcastle upon Tyne was drawn from the biochemistry database of the local hospital. The names and date of births of these patients were used to draw corresponding hematological data, including hemoglobin, white blood cell count, mean corpuscular volume (MCV), and platelet count, conducted on the same day or within a week of the valproate level measurement. RESULTS: : The data from 126 patients were analyzed. The prevalence of thrombocytopenia (platelet count, <150,000/microL) was found to be approximately 5%. In female subjects, a significant negative correlation was found between serum valproate level and platelet count; also, a positive correlation between valproate level and MCV was found. Neither correlation was found in male subjects. The risk of a low platelet count was found to be significantly increased at serum valproate level above 80 microg/mL in female subjects. The regression analysis in female patients showed a trend toward fall in platelet count and an increase in MCV with increasing age. CONCLUSIONS: In psychiatric patients on valproate therapy, close monitoring of full blood count is required in women particularly at valproate serum level above 80 microg/mL. This may be particularly important in older patients.
