WITHDRAWN: Antiglucocorticoid treatments for mood disorders
Antiglucocorticoids may have antidepressant effects and have been reported to be efficacious in the treatment of severe psychiatric disorders. The efficacy and safety of antiglucocorticoid treatments for mood disorders is the subject of this systematic review. To compare the efficacy and safety of antiglucocorticoid agents in the treatment of mood episodes (manic, mixed affective or depressive) with placebo or alternative drug treatment in mood disorders. CCDANCTR-Studies and CCDANCTR-References were searched on 11-9-2007. Additional searches of electronic databases were conducted in December 2006. Conference proceedings were searched. Experts and pharmaceutical companies were contacted. Randomised controlled trials comparing antiglucocorticoid drugs in the treatment of mood episodes with placebo or alternative drug treatment in mood disorders were selected. Data were extracted and the methodological quality of each study was assessed independently by two review authors. Meta-analyses were performed using Review Manager software. Relative risk (RR) with 95% confidence intervals (CI) were calculated for dichotomous outcomes. For continuous data, weighted mean differences (WMD) were calculated. Nine studies met criteria for inclusion. A number of drugs were examined, including mifepristone [RU-486], ketoconazole, metyrapone and DHEA. Three trials were in patients with psychotic major depression (pMDD), five trials in non-psychotic major depression and one trial in bipolar disorder. When examining all trials together across all affective episodes, there was no significant difference in the overall proportion of patients responding to antiglucocorticoid treatment over placebo, although the mean change in HAM-D scores indicated a significant difference in favour of treatment (WMD -4.54, 95%CI -6.78 to -2.29). Of the five trials in non-psychotic depression (unipolar or bipolar), there was a significant difference favouring treatment (HAM-D 50% reduction: RR 0.72, 95%CI 0.56 to 0.91). In pMDD, there was no evidence of an overall antidepressant effect (HAM-D 50% reduction: RR 0.98, 95%CI 0.79 to 1.22) or an effect on overall psychopathology (BPRS 30% reduction: RR 0.96, 95%CI 0.76 to 1.22). In these subtypes, the mean change in HAM-D indicated a significant difference in favour of treatment. The use of antiglucocorticoids in the treatment of mood disorders is at the proof-of-concept stage. Considerable methodological differences exist between studies with respect to the compounds used and the patient cohorts studied. Results in some diagnostic subtypes are promising and warrant further investigation to establish the clinical utility of these drugs in the treatment of mood disorders.
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[Show abstract] [Hide abstract] ABSTRACT: Individual differences in the psychobiology of the stress response have been linked to behavior problems in youth yet most research has focused on single signaling molecules released by either the hypothalamic-pituitary-adrenal axis or the autonomic nervous system. As our understanding about biobehavioral relationships develops it is clear that multiple signals from the biological stress systems work in coordination to affect behavior problems. Questions are raised as to whether coordinated effects should be statistically represented as ratio or interactive terms. We address this knowledge gap by providing a theoretical overview of the concepts and rationales, and illustrating the analytical tactics. Salivary samples collected from 446 youth aged 11-12 were assayed for salivary alpha-amylase (sAA), dehydroepiandrosterone-sulfate (DHEA-s) and cortisol. Coordinated effect of DHEA-s and cortisol, and coordinated effect of sAA and cortisol on externalizing and internalizing problems (Child Behavior Checklist) were tested with the ratio and the interaction approaches using multi-group path analysis. Findings consistent with previous studies include a positive association between cortisol/DHEA-s ratio and internalizing problems; and a negative association between cortisol and externalizing problems conditional on low levels of sAA. This study highlights the importance of matching analytical strategy with research hypothesis when integrating salivary bioscience into research in behavior problems. Recommendations are made for investigating multiple salivary analytes in relation to behavior problems.
- "The neuroprotective and antiglucocorticoid effects of DHEA(-s) may give rise to the observed opposite relations between behavior problems and cortisol versus DHEA(s ). DHEA(-s) has been found to be lowered in depression (Goodyer et al., 1996; Michael et al., 2000 ) and DHEA(s ) supplementation has antidepressant effects (Wolkowitz et al., 1997; Gallagher et al., 2008). In contrast, cortisol is positively associated, albeit not consistently, with internalizing symptoms such as depression and anxiety (Duran et al., 2009; Vreeburg et al., 2010 ). "
[Show abstract] [Hide abstract] ABSTRACT: Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service.Methods/design: Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Asberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone. Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments.Trial registration: Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.
- "The study extends research in this area by exploring the translatability of the proof of concept study described above  to an outpatient, primary and secondary care, UK National Health Service (NHS) population. To date, all published studies of the use of antiglucocorticoids in patients with TRD have used short treatment periods of 1-3 weeks  , which can appear counter-intuitive in such a potentially chronic condition . However, evidence suggests that the clinical effects of antiglucocorticoids on HPA axis function persist after their prescription has ceased [34,35]. "
[Show abstract] [Hide abstract] ABSTRACT: Major depression is a heterogeneous disorder, both in terms of symptoms, ranging from anhedonia to cognitive impairment, and in terms of pathogenesis, with many interacting genetic, epigenetic, developmental and environmental causes. Accordingly, it seems unlikely that depressive states could be fully controlled by a drug possessing one discrete mechanism of action and, in the wake of disappointing results with several classes of highly selective agent, multi-modal treatment concepts are attracting attention. As concerns pharmacotherapy, there are essentially two core strategies. First, multi-target antidepressants that act via two or more complementary mechanisms and, second, polypharmacy, which refers to co-administration of two distinct drugs, usually in separate pills. Both multi-target agents and polypharmacy ideally couple a therapeutically unexploited action to a clinically established mechanism in order to enhance efficacy, moderate side-effects, accelerate onset of action and treat a broader range of symptoms. The melatonin MT1/MT2 agonist and 5-HT2C antagonist, agomelatine, which is effective in the short- and long-term treatment of depression, exemplifies the former approach, while evidence-based polypharmacy is illustrated by the adjunctive use of second-generation antipsychotics with serotonin reuptake inhibitors for treatment of resistant depression. Histone acetylation and methylation, ghrelin signalling, inflammatory modulators, metabotropic glutamate-7 receptors and trace amine-associated-1 receptors comprise attractive substrates for new multi-target and polypharmaceutical strategies. The present article outlines the rationale underpinning multi-modal approaches for treating depression, and critically compares and contrasts the pros and cons of established and potentially novel multi-target vs. polypharmaceutical treatments. On balance, the former appear the most promising for the elaboration, development and clinical implementation of innovative concepts for the more effective management of depression.
- "Note, however, that thyroid hormones are little used today and that data for oestrogen agonists (mostly tested in peri-menopausal women) remain preliminary. Moreover, despite considerable efforts and a strong rationale, clinical studies with mefepristone (a glucocorticoid antagonist) and metyrapone (an inhibitor of glucocorticoid synthesis) – which should protect cells from detrimental effects of excessive stress-induced corticosterone release and favour cognitive performance – have not been brought to fruition, even in patients showing psychotic depression, where the hypothalamic-pituitary axis activity is disinhibited (Millan, 2006; Gallagher et al., 2008; Schatzberg and Lindley, 2008). Other examples (not depicted inTable 2) of absent multi-target lookalikes for a clinically tested SSRI augmentation strategy include instances where the drug added on: (1) has a poorly defined mechanism; (2) acts itself in a multi-target fashion; (3) the association has yielded ambivalent experimental and clinical data providing only a modest incentive to launch a discovery programme for an equivalent multi-target agent. "