SummaryBackgroundThe use of electroconvulsive therapy (ECT) is limited by concerns about its cognitive adverse effects. Preliminary evidence suggests that administering the glutamate antagonist ketamine with ECT might alleviate cognitive adverse effects and accelerate symptomatic improvement; we tested this in a randomised trial of low-dose ketamine.MethodsIn this multicentre, randomised, parallel-group study in 11 ECT suites serving inpatient and outpatient care settings in seven National Health Service trusts in the North of England, we recruited severely depressed patients, who were diagnosed as having unipolar or bipolar depressive episodes defined as moderate or severe by DSM-IV criteria, aged at least 18 years, and were able and willing to provide written consent to participate in the study. Patients were randomly assigned (1:1) to ketamine (0·5 mg/kg intravenous bolus) or saline adjunctive to the anaesthetic for the duration of their ECT course. Patients and assessment and ECT treatment teams were masked to treatment allocation, although anaesthetists administering the study medication were not. We analysed the primary outcome, Hopkins Verbal Learning Test-Revised delayed verbal recall (HVLT-R-DR) after four ECT treatments, using a Gaussian repeated measures model in all patients receiving the first ECT treatment. In the same population, safety was assessed by adverse effect monitoring. This trial was registered with International Standard Randomised Controlled Trial Number, number ISRCTN14689382.FindingsBetween early December, 2012, and mid-June, 2015, 628 patients were screened for eligibility, of whom 79 were randomly assigned to treatment (40 in the ketamine group vs 39 in the saline group). Ketamine (mean 5·17, SD 2·92), when compared with saline (5·54, 3·42), had no benefit on the primary outcome (HVLT-R-DR; difference in means −0·43 [95% CI −1·73 to 0·87]). 15 (45%) of 33 ketamine-treated patients compared with 10 (27%) of 37 patients receiving saline experienced at least one adverse event which included two (6%) of 33 patients who had ketamine-attributable transient psychological effects. Psychiatric adverse events were the most common in both groups (six [27%] of 22 adverse events in the ketamine group vs seven [54%] of 13 in the saline group).InterpretationNo evidence of benefit for ketamine was found although the sample size used was small; however, the results excluded greater than a small to moderate benefit with 95% confidence. The results do not support the use of adjunctive low-dose ketamine in routine ECT treatment.FundingNational Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

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Aims and method To investigate the use of additional conditions attached to community treatment orders (CTOs) and whether they influence the process of recall to hospital. We conducted a retrospective descriptive survey of the records and associated paperwork of all the CTOs started in the trust in the year from January 2010. Each CTO was followed up for 12 months.Results A total of 65 CTOs were included in the study; 25 patients were recalled during the study and all but one of these had their CTO revoked and remained in hospital. Each patient whose CTO was revoked had experienced a relapse in their condition. Many patients had not complied with CTO conditions prior to relapsing and could potentially have been recalled earlier.Clinical implications Our findings suggest that the breaching of additional CTO conditions does not tend to result in a patient's recall to hospital. This has implications regarding how the workings of CTOs are explained to patients and regarding the utility of additional conditions more generally.

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.

BackgroundThere is a robust empirical evidence base supporting the acute efficacy of electroconvulsive therapy (ECT) for severe and treatment resistant depression. However, a major limitation, probably contributing to its declining use, is that ECT is associated with impairment in cognition, notably in anterograde and retrograde memory and executive function. Preclinical and preliminary human data suggests that ketamine, used either as the sole anaesthetic agent or in addition to other anaesthetics, may reduce or prevent cognitive impairment following ECT. A putative hypothesis is that ketamine, through antagonising glutamate receptors, protects from excess excitatory neurotransmitter stimulation during ECT. The primary aim of the ketamine-ECT study is to investigate whether adjunctive ketamine can attenuate the cognitive impairment caused by ECT. Its secondary aim is to examine if ketamine increases the speed of clinical improvement with ECT.Methods/DesignThe ketamine ECT study is a multi-site randomised, placebo-controlled, double blind trial. It was originally planned to recruit 160 moderately to severely depressed patients who had been clinically prescribed ECT. This recruitment target was subsequently revised to 100 patients due to recruitment difficulties. Patients will be randomly allocated on a 1:1 basis to receive either adjunctive ketamine or saline in addition to standard anaesthesia for ECT. The primary neuropsychological outcome measure is anterograde verbal memory (Hopkins Verbal Learning Test-Revised delayed recall task) after 4 ECT treatments. Secondary cognitive outcomes include verbal fluency, autobiographical memory, visuospatial memory and digit span. Efficacy is assessed using observer and self-report efficacy measures of depressive symptomatology. The effects of ECT and ketamine on cortical activity during cognitive tasks will be studied in a sub-sample using functional near-infrared spectroscopy (fNIRS).DiscussionThe ketamine-ECT study aims to establish whether or not adjunctive ketamine used together with standard anaesthesia for ECT will significantly reduce the adverse cognitive effects observed after ECT. Potential efficacy benefits of increased speed of symptom improvement and a reduction in the number of ECT treatments required will also be assessed, as will safety and tolerability of adjunctive ketamine. This study will provide important evidence as to whether adjunctive ketamine is routinely indicated for ECT given for depression in routine NHS clinical practice.Trial RegistrationCurrent Controlled Trials: ISRCTN14689382 (assigned 30/07/2012); EudraCT Number: 2011-005476-41