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.
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.
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.
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.
Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.
Background
Depressed patients who do not respond to second-line antidepressant drugs are characterised as suffering from treatment-refractory depression (TRD). Chronic psychosocial stress ...hypothalamic–pituitary–adrenal (HPA) axis dysfunction is associated with attenuated responses to antidepressants. Corticosteroid co-administration reduces the increase in forebrain 5-hydroxytryptamine with selective serotonin reuptake inhibitors, whereas antiglucocorticoids have the opposite effect. A Cochrane review suggesting that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD included a pilot study of the cortisol synthesis inhibitor, metyrapone. The
A
ntiglucocorticoid augmentation of anti
D
epressants in
D
epression (ADD Study) was a multicentre randomised placebo-controlled trial of metyrapone augmentation of serotonergic antidepressants in patients with TRD.
Objective
To determine the efficacy and safety of augmentation of standard serotonergic antidepressants with metyrapone 500 mg twice a day for 3 weeks in patients with TRD.
Methods
A total of 165 patients with moderate to severe TRD aged 18–65 years were randomised to metyrapone 500 mg twice daily or placebo for 3 weeks, in addition to ongoing serotonergic antidepressants. The primary outcome was improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation estimated using analysis of covariance. Secondary outcomes included the degree of persistence of treatment effect for up to 6 months, and also safety and tolerability of metyrapone. ADD included substudies investigating the potential mechanism of action of metyrapone, and utilised a comparator group of healthy participants.
Results
The estimated mean difference for each of our study outcomes between randomised groups, 5 weeks post randomisation (allowing for variation between centres and whether or not patients originate from primary or secondary care) was MADRS –0.51 95% confidence interval (CI) –3.48 to 2.46; Beck Depression Inventory (BDI) –2.65 (95% CI –6.41 to 1.10); Clinical Anxiety Scale 0.46 (95% CI –1.20 to 2.12); State–Trait Anxiety Inventory 1.2 (95% CI –0.6 to 3.0); European Quality of Life-5 Dimensions 0.015 (95% CI –0.069 to 0.099); EuroQol visual analogue scale 5.6 (95% CI –0.7 to 12.0); and Young Mania Rating Scale –0.04 (95% CI –0.52 to 0.45). The differences were not statistically significant and were small in relation to the change from baseline in both groups that was observed immediately after completion of therapy. Endocrinological data required for compliance assessment are not yet available. HPA function, similar in patients and control subjects, was not associated with differing clinical responses. Neuropsychological impairments were found, along with changes in brain structure and function, but no effect of metyrapone was seen on these measures.
Discussion
The inclusion criteria led to the sample being broadly representative of patients with TRD, within the UK NHS, with high anxiety and BDI scores. Metyrapone augmentation of antidepressants is not efficacious for outpatients with TRD who are moderately depressed. There was no obvious benefit associated with the use of metyrapone, either on the primary outcome or over the period of follow-up, and this negative result extended to other secondary outcomes. Metyrapone was well tolerated. There were no serious adverse events attributable to it and adverse events were as common with the placebo. HPA axis function was not associated with differing clinical or neuropsychological outcomes.
Conclusions
The results of the study suggest that although metyrapone augmentation was well tolerated, it is ineffective in the treatment of refractory depression. This finding is contrary to a previous proof of principle study in more acutely unwell patients. Future research should consider whether or not antiglucocorticoid treatments, such as metyrapone, should be targeted at patients with confirmed hypercortisolaemia.
Trial registration
Current Controlled Trials ISRCTN45338259.
Funding details
This study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.
Background The Quality and Outcomes Framework (QOF) incentivises general practices in England to provide proactive care for people with serious mental illness (SMI) including schizophrenia, bipolar ...disorder and other psychoses. Better proactive primary care may reduce the risk of psychiatric admissions to hospital, but this has never been tested empirically. Methods The QOF data set included 8234 general practices in England from 2006/2007 to 2010/2011. Rates of hospital admissions with primary diagnoses of SMI or bipolar disorder were estimated from national routine hospital data and aggregated to practice level. Poisson regression was used to analyse associations. Results Practices with higher achievement on the annual review for SMI patients (MH9), or that performed better on either of the two lithium indicators for bipolar patients (MH4 or MH5), had more psychiatric admissions. An additional 1% in achievement rates for MH9 was associated with an average increase in the annual practice admission rate of 0.19% (95% CI 0.10% to 0.28%) or 0.007 patients (95% CI 0.003 to 0.01). Conclusions The positive association was contrary to expectation, but there are several possible explanations: better quality primary care may identify unmet need for secondary care; higher QOF achievement may not prevent the need for secondary care; individuals may receive their QOF checks postdischarge rather than prior to admission; individuals with more severe SMI may be more likely to be registered with practices with better QOF performance; and QOF may be a poor measure of the quality of care for people with SMI.
Background
Serious mental illness (SMI) is a set of chronic enduring conditions including schizophrenia and bipolar disorder. SMIs are associated with poor outcomes, high costs and high levels of ...disease burden. Primary care plays a central role in the care of people with a SMI in the English NHS. Good-quality primary care has the potential to reduce emergency hospital admissions, but also to increase elective admissions if physical health problems are identified by regular health screening of people with SMIs. Better-quality primary care may reduce length of stay (LOS) by enabling quicker discharge, and it may also reduce NHS expenditure.
Objectives
We tested whether or not better-quality primary care, as assessed by the SMI quality indicators measured routinely in the Quality and Outcomes Framework (QOF) in English general practice, is associated with lower rates of emergency hospital admissions for people with SMIs, for both mental and physical conditions and with higher rates of elective admissions for physical conditions in people with a SMI. We also tested the impact of SMI QOF indicators on LOS and costs.
Data
We linked administrative data from around 8500 general practitioner (GP) practices and from Hospital Episode Statistics for the study period 2006/7 to 2010/11. We identified SMI admissions by a main
International Classification of Diseases
, 10th revision (ICD-10) diagnosis of F20–F31. We included information on GP practice and patient population characteristics, area deprivation and other potential confounders such as access to care. Analyses were carried out at a GP practice level for admissions, but at a patient level for LOS and cost analyses.
Methods
We ran mixed-effects count data and linear models taking account of the nested structure of the data. All models included year indicators for temporal trends.
Results
Contrary to expectation, we found a positive association between QOF achievement and admissions, for emergency admissions for both mental and physical health. An additional 10% in QOF achievement was associated with an increase in the practice emergency SMI admission rate of approximately 1.9%. There was no significant association of QOF achievement with either LOS or cost. All results were robust to sensitivity analyses.
Conclusions
Possible explanations for our findings are (1) higher quality of primary care, as measured by QOF may not effectively prevent the need for secondary care; (2) patients may receive their QOF checks post discharge, rather than prior to admission; (3) people with more severe SMIs, at a greater risk of admission, may select into practices that are better organised to provide their care and which have better QOF performance; (4) better-quality primary care may be picking up unmet need for secondary care; and (5) QOF measures may not accurately reflect quality of primary care. Patient-level data on quality of care in general practice is required to determine the reasons for the positive association of QOF quality and admissions. Future research should also aim to identify the non-QOF measures of primary care quality that may reduce unplanned admissions more effectively and could potentially be incentivised.
Funding
The National Institute for Health Research Health Services and Delivery Research programme.
This study explores the experiences of people caring for, or supporting, relatives described as suffering severe mental illness. For the purposes of the research this has been defined as ...schizophrenia or bipolar disorder (manic depression). Qualitative method has been used to emphasise the powerful nature of the experiences that the subjects encountered. The study has innovatively used the researcher's own caring career which unfolded during her period of study registration. The difficulties and advantages of this approach have been examined within a feminist framework.The research also explores the experiences of a small number of carers of people with dementia as an aid to highlighting the particular needs of those supporting people with severe mental illhealth. The data is presented in terms of the carer's path through the mental health system. It traces the cyclical periods of despondency and hope that accompanying the service user's symptoms.Since the implementation of the NHS and Community Care Act 1990 family supporters of sick and disabled members have been afforded recognition as carers. Their often tireless provision of assistance, and their cooperation with statutory services are essential to the success of the policy of non-institutional care. Community Care has been put forward as the ideal for a whole range of service user groups, many of which were previously catered for in large hospitals. While it would appear prudent for the state to support people who perform this difficult and demanding task, at no cost to the tax payer, the study shows that carers' practical and emotional needs continue to be inadequately addressed. The experience of carers is conceptualised as attachment violation. Discussion explores the destructive dimension of severe mental illness which attacks people's relationships, cutting both users and carers off from support at a time when it is most needed. Carers found themselves dealing with distressing changes in their relative's behaviour, which might lead to the user and others being placed at risk. Despite this, carers' attempts to seek help from outside were often rebuffed.
The Byzantine antiquities of the Pontus have received little more than a passing glance from either travellers or archaeologists. With the exception of the town of Trebizond, the monuments of which ...have now been subject to study in some detail, and the monastery of Sumela which has always attracted the attention of travellers, the only published works on the subject are the article by Professor Talbot Rice containing the results of his survey journey in 1929, and the book which he wrote in co-operation with Millet. The “Studia Pontica” of Cumont and Anderson is concerned primarily with classical antiquities although Cumont in his section makes frequent reference to medieval antiquities; and the “Church of Trebizond” by the last Metropolitan of the town, Chrysanthos, is concerned more with history than with descriptions of the monuments. The not inconsiderable body of travellers to Trebizond and eastern Turkey went there, for the most part, by sea and followed one or other of the branches of the caravan road running south-eastwards to Erzurum, and on into Persia and Central Asia. It may, however, be of use to bring these accounts up to date in so far as we have followed in the footsteps of earlier travellers.
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BFBNIB, INZLJ, NMLJ, NUK, PNG, UL, UM, UPUK, ZRSKP
A number of experimental models for the study of the pathogenesis of the restenotic process have been developed, although many fail to correlate the time courses of both functional and morphological ...alterations following balloon injury. Our aim was to develop a rabbit model of balloon injury, which studied both of these alterations in detail.
Male New Zealand White rabbits (12 weeks old) were fed a high-cholesterol diet for 4 weeks, after which they were subjected to balloon injury of the left subclavian artery. After surgery the animals were returned to a normal diet and sacrificed 2, 7, 15 or 30 days after angioplasty. Two further groups of animals were sacrificed either after 4 weeks of high-cholesterol feeding (no angioplasty) or 2 days after a sham angioplasty operation. Angioplasty-induced changes in vasoconstrictor to 5-hydroxytryptamine (5-HT) and KCl and endothelium-dependent (ACh and calcimycin) and endothelium-independent (sin-1) vasodilator responses were assessed in isolated vessel rings. Morphological analysis of the size and composition of neointima was also made at each timepoint.
Hypercholesterolaemia reduced the responsiveness of the subclavian arteries to the endothelium-dependent vasodilators carbachol and calcimycin; however, this responsiveness was restored after 7 days of a normal diet. The response to carbachol remained depressed in angioplastied arteries until 30 days after angioplasty, whereas recovery of relaxation to calcimycin was unaffected by angioplasty. Responses to 5-HT, KCl and sin-1 were unchanged by either hypercholesterolaemia or angioplasty. Morphological studies demonstrated the development of neointima in all rabbits after 7 days, reaching a maximum size after 15 days. All neointima stained for a smooth muscle actin. Accumulation of macrophages appeared in the media after 7 days and was present in the neointima after 15 days, and subsequently declined. Proliferating smooth-muscle cells were evident in the media 2 days after angioplasty, and in the neointima fro 7 days onwards.
In the rabbit subclavian artery, we have developed a model that describes fully the temporal development and characteristics of an intimal cellular response and functional changes following balloon injury.
Thrombin, a potent stimulator of smooth muscle cell proliferation and inhibitor of endothelial cell growth, has been implicated as an important mediator of restenosis after angioplasty. Acute ...administration of the thrombin inhibitor r-hirudin reduced restenosis in animal models of angioplasty, possibly by inhibiting smooth muscle cell proliferation. Because thrombin-induced proliferation requires prolonged exposure to the agonist, it was hypothesized that a greater reduction in lesion size could be achieved by chronic administration of r-hirudin.
To determine whether prolonged treatment with r-hirudin would reduce lesion size and improve vascular function in a rabbit model of neointimal proliferation.
Male New Zealand white rabbits were fed a high-cholesterol diet for 4 weeks, after which they were subjected to balloon injury of the left subclavian artery. The rabbits were assigned to one of three groups: control (no drug); acute r-hirudin treatment (0.33 mg/kg intravenously plus 0.48 mg/kg per h subcutaneously for 24 h); or chronic r-hirudin treatment (0.33 mg/kg intravenously plus 0.6 mg/kg per h subcutaneously for 28 days). After surgery the rabbits were fed a normal diet and killed 30 days later. Left (angioplastied) and right (control) subclavian arteries were removed for morphological and functional analysis.
Angioplasty in control, untreated rabbits produced large neointimal lesions 15.0 +/- 1.8% of the area within the external elastic lamina (EEL), comprised mainly of smooth muscle cells (34 +/- 16 cells/section) and lipid-rich macrophage or foam cells (118 +/- 51 cells/section). Acute r-hirudin treatment neither inhibited smooth muscle cell proliferation (35 +/- 12 cells/section) nor reduced neointimal lesion size (23.5 +/- 4.6% of the area within the EEL). Chronic r-hirudin treatment significantly increased the number of proliferating cells (55 +/- 15 cells/section, P < 0.05) and the size of the lesions (28.5 +/- 5.6% of the area within the EEL, P < 0.05). Further more, treatment with r-hirudin appeared to exacerbate, rather than improve, angioplasty-induced functional alterations.
Prolonged treatment with r-hirudin neither inhibits vascular smooth muscle cell proliferation in rabbits after angioplasty of the left subclavian artery nor reduces the size of neointimal lesions. Furthermore, treatment with r-hirudin might impair endothelial cell function after angioplasty. This suggests that prolonged thrombin inhibition using this r-hirudin regimen is not suitable as an antirestenotic intervention.
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