Antidepressant augmentation with metyrapone for treatment-resistant depression (the ADD study): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression. METHODS: This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18-65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2-10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31. FINDINGS: Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 [83%] in the metyrapone and 74 [90%] in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points [95% CI 19·2-24·4] in the metyrapone group vs 22·6 points [20·1-24·8] in the placebo group; adjusted mean difference of -0·51 points [95% CI -3·48 to 2·46]; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug. INTERPRETATION: Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic-pituitary-adrenal axis abnormalities. FUNDING: Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.

Perceived reasons for and consequences of substance abuse among patients with psychosis.

BACKGROUND: Substance use is a common comorbidity with psychotic illnesses. Although several theories exist to explain this link, individual reasons for use may differ. The aim of this study was to evaluate patient perceptions of the reasons for and consequences of their substance use in patients with psychosis and compare them with those of an age-, sex-, and tobacco use-matched control sample without psychosis. METHOD: Consecutively admitted patients were divided into 2 groups, those who had substance dependence without psychosis (n = 32), admitted in our addiction unit, and those who had psychotic illness with substance dependence, admitted in our inpatient psychosis unit and referred to as the dual-diagnosis group (n = 62). Patients were administered the Schedules for Clinical Assessment in Neuropsychiatry for ICD-10 Diagnostic Criteria for Research to confirm schizophrenia, bipolar affective disorder, and substance dependence diagnoses and were asked open-ended questions to evaluate the perceived reasons for and consequences of their substance use. The study was conducted from July to September 2006. RESULTS: There were significant differences between the 2 groups in reasons for maintenance and relapse of both cannabis use and alcohol use, the 2 most common substances. While the substance dependence without psychosis group attributed both maintenance and relapse to external factors such as nature of work, social milieu, or peer pressure, the dual-diagnosis group attributed them to internal factors such as enhancement of positive mood and alleviation of withdrawal effects. CONCLUSIONS: Individuals with psychosis have greater vulnerability to internal factors, which may maintain substance use. Targeting perceived internal factors may play a useful role in management and possibly identification and prevention of psychosis in vulnerable individuals in the future.