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

McAllister‐Williams, R. Hamish; Anderson, Ian M.; Finkelmeyer, Andreas; Gallagher, Peter; Grunze, Heinz; Haddad, Peter M.; Hughes, Tom; Lloyd, Adrian J.; Mamasoula, Chrysovalanto; McColl, Elaine; Pearce, Simon H. S.; Siddiqi, Najma; Sinha, Baxi Neeraj Prasad; Steen, Nick; Wainwright, June; Winter, Fiona H; Ferrier, I. Nicol; Watson, Stuart

doi:10.1016/s2215-0366(15)00436-8

Cited by 43 publications

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“…4 A recent UK RCT in patients with a similar degree of treatment resistance as in the patients in this study (mean MGHS score of 4.7), although with a lesser severity of depression (baseline mean MADRS score of 28), reported a 21% response rate and a 16% remission rate after 5 weeks in patients treated with placebo or metyrapone DISCUSSION NIHR Journals Library www.journalslibrary.nihr.ac.uk augmentation of ongoing antidepressant treatment. 162 This suggests that patients in this study received considerable clinical benefit attributable to ECT treatment. However, the degree of improvement was less than is often reported with ECT; for example, Kellner et al 27 found a 65% remission rate with bilateral ECT, and a meta-analysis of seven cohort studies 8 found a 65% remission rate for patients without previous pharmacotherapy failure and a 48% remission rate for those with treatment resistance.…”

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confidence: 82%

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

et al. 2017

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BackgroundElectroconvulsive therapy (ECT) is the most effective acute treatment for severe depression, but there are concerns about its adverse cognitive effects. ECT may impair cognition through stimulation of glutamate receptors, and preliminary evidence has suggested that ketamine, a glutamate antagonist, may alleviate these effects. Ketamine has been shown to have a rapid, but temporary, antidepressant effect after a single infusion.ObjectiveTo determine the efficacy and safety of adjunctive low-dose ketamine to reduce cognitive impairments caused by ECT and, secondarily, to improve symptomatic outcome.DesignMulticentre, two-arm, parallel-group, patient-randomised, placebo-controlled superiority trial.SettingEleven ECT suites based in seven NHS trusts in the north of England.ParticipantsSeverely depressed hospitalised patients or outpatients who received ECT as part of their usual clinical care.InterventionsPatients were randomised to ketamine (0.5 mg/kg) or saline as an adjunct to their anaesthetic for their ECT course in a 1 : 1 ratio.Main outcome measuresThe primary outcome was delayed verbal recall on the Hopkins Verbal Learning Task – Revised (HVLT-R) after four ECT treatments (mid-ECT), analysed using a Gaussian repeated measures model. Secondary outcomes included autobiographical, working and visual memory and verbal fluency, symptoms and quality of life; assessments occurred at mid-ECT, end of treatment and 1 and 4 months after the last ECT. Neuropsychological function was compared with that of healthy control subjects and a functional near-infrared spectroscopy (fNIRS) substudy investigated prefrontal cortex function. A patient survey of study participation was carried out.ResultsSeventy-nine severely depressed patients were randomised to ketamine (0.5 mg/kg) or saline as an adjunct to their anaesthetic for their ECT course; the modified intention-to-treat sample included 70 patients. Compared with saline, adjunctive ketamine had no significant effect on HVLT-R delayed recall [treatment effect difference –0.43, 95% confidence interval (CI) –1.73 to 0.87], other neuropsychological outcomes, improvement in depression [difference in Montgomery–Åsberg Depression Rating Scale (MADRS) score of 0.44, 95% CI –1.03 to 1.91], the number of ECT treatments to remission (MADRS score of ≤ 10: 0.83, 95% CI –3.2 to 4.9), anxiety symptoms or quality of life. By the end of ECT treatment, 37% (saline 35%, ketamine 39%) of patients had remitted. Tolerability was similar in the two treatment arms; two patients had isolated transient psychological effects attributable to ketamine. Preliminary fNIRS analysis found that patients had blunted prefrontal cortical haemodynamic responses compared with control subjects during a verbal fluency task at baseline; this was further diminished at mid-ECT without modulation by ketamine. Greater haemodynamic responsivity to ECT appeared to be associated with a better clinical response. The majority of patients surveyed reported a positive experience of study participation.ConclusionsThe results of the study do not support the use of adjunctive ketamine in routine ECT treatment in the NHS. Although no evidence of benefit was found for ketamine, moderate benefits or harms cannot be excluded, as recruitment was < 50% of that planned, limiting the power of the clinical trial. Low numbers also meant that in the fNIRS substudy the effect of ketamine could not be assessed and the other findings must be viewed as preliminary. Included patients were younger than those not included and had only limited cognitive impairment with ECT, limiting generalisation to more cognitively compromised patients. fNIRS appeared to be a potentially feasible portable brain imaging technology in severely ill patients and further research is warranted to investigate its clinical utility.Trial registrationCurrent Controlled Trials ISRCTN14689382.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

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Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

et al. 2017

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“…One third were recruited as part of the above mentioned CFS study, with the remaining two thirds being recruited as healthy volunteers in a clinical trial investigating treatment-resistant major depression (McAllister-Williams et al, 2016). Recruitment for both studies happened during approximately the same time period.…”

Section: Methodsmentioning

confidence: 99%

Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study

Finkelmeyer

Maclachlan

et al. 2018

NeuroImage: Clinical

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ObjectiveInvestigate global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods.MethodsForty-two patients with CFS and thirty healthy volunteers were scanned on a 3-Tesla MRI scanner. Anatomical MRI scans were segmented, normalized and submitted to a VBM analysis using randomisation methods. Group differences were identified in overall segment volumes and voxel-wise in spatially normalized grey matter (GM) and white matter (WM) segments.ResultsAccounting for total intracranial volume, patients had larger GM volume and lower WM volume. The voxel-wise analysis showed increased GM volume in several structures including the amygdala and insula in the patient group. Reductions in WM volume in the patient group were seen primarily in the midbrain, pons and right temporal lobe.ConclusionElevated GM volume in CFS is seen in areas related to processing of interoceptive signals and stress. Reduced WM volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem.

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“…These appear promising 178. Antiglucocorticoid compounds, including ketoconazole179 and metyrapone,180 have been investigated for depression, but both have drawbacks with their side effect profile and the clinical potential of metyrapone is uncertain. Mifepristone181 and the corticosteroids fludrocortisone and spironolactone,182 and dexamethasone and hydrocortisone183 may also be effective in treating depression in the short term.…”

Section: Future Prospectsmentioning

confidence: 99%

Biomarkers for depression: recent insights, current challenges and future prospects

Strawbridge¹,

Young²,

Cleare³

2017

NDT

306

156

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A plethora of research has implicated hundreds of putative biomarkers for depression, but has not yet fully elucidated their roles in depressive illness or established what is abnormal in which patients and how biologic information can be used to enhance diagnosis, treatment and prognosis. This lack of progress is partially due to the nature and heterogeneity of depression, in conjunction with methodological heterogeneity within the research literature and the large array of biomarkers with potential, the expression of which often varies according to many factors. We review the available literature, which indicates that markers involved in inflammatory, neurotrophic and metabolic processes, as well as neurotransmitter and neuroendocrine system components, represent highly promising candidates. These may be measured through genetic and epigenetic, transcriptomic and proteomic, metabolomic and neuroimaging assessments. The use of novel approaches and systematic research programs is now required to determine whether, and which, biomarkers can be used to predict response to treatment, stratify patients to specific treatments and develop targets for new interventions. We conclude that there is much promise for reducing the burden of depression through further developing and expanding these research avenues.

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

Abstract: Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.

Cited by 43 publications

References 36 publications

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study

Biomarkers for depression: recent insights, current challenges and future prospects

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