Efficacy and safety of ketamine-assisted electroconvulsive therapy in major depressive episode: a systematic review and network meta-analysis.

OBJECTIVE: To meta-analyze clinical efficacy and safety of ketamine compared with other anesthetic agents in the course of electroconvulsive therapy (ECT) in major depressive episode (MDE). METHODS: PubMed/MEDLINE, Cochrane Library, Embase, GoogleScholar, and US and European trial registries were searched from inception through May 23, 2023, with no language limits. We included RCTs with (1) a diagnosis of MDE; (2) ECT intervention with ketamine and/or other anesthetic agents; and (3) measures included: depressive symptoms, cognitive performance, remission or response rates, and serious adverse events. Network meta-analysis (NMA) was performed to compare ketamine and 7 other anesthetic agents. Hedges' g standardized mean differences (SMDs) were used for continuous measures, and relative risks (RRs) were used for other binary outcomes using random-effects models. RESULTS: Twenty-two studies were included in the systematic review. A total of 2322 patients from 17 RCTs were included in the NMA. The overall pooled SMD of ketamine, as compared with propofol as a reference group, was -2.21 (95% confidence interval [CI], -3.79 to -0.64) in depressive symptoms, indicating that ketamine had better antidepressant efficacy than propofol. In a sensitivity analysis, however, ketamine-treated patients had a worse outcome in cognitive performance than propofol-treated patients (SMD, -0.18; 95% CI, -0.28 to -0.09). No other statistically significant differences were found. CONCLUSIONS: Ketamine-assisted ECT is tolerable and may be efficacious in improving depressive symptoms, but a relative adverse impact on cognition may be an important clinical consideration. Anesthetic agents should be considered based on patient profiles and/or preferences to improve effectiveness and safety of ECT use.

Ketamine or ECT? What Have We Learned From the KetECT and ELEKT-D Trials?

1. Two recent clinical trials, KetECT and ELEKT-D, compared the effectiveness of ketamine and electroconvulsive therapy (ECT) for major depressive disorder. Notably, these trials reported marked differences in ECT's clinical outcomes of, with remission rates of 63% for KetECT and a strikingly lower rate of 22% for ELEKT-D, while the remission rates for ketamine were 46% and 38%, respectively. Considering that the primary objective of both trials was to compare the standard treatment (ECT) with an experimental intervention (ketamine), it is crucial to highlight the pronounced disparities in ECT's clinical outcomes. This article offers a comprehensive comparison of these trials while also exploring how patient characteristics, treatment protocols, and study designs may contribute to such pronounced outcome discrepancies. These differences highlight the heterogeneous nature of depression and underscore the need for personalized treatments. These studies also provide valuable insights into identifying the most suitable candidates for ketamine and ECT.

Clinical and Legal Differences in the Use of Involuntary Electroconvulsive Therapy for Life-Threatening Illness Across European Countries.

OBJECTIVES: Electroconvulsive therapy (ECT) can be life-saving in situations where patients are at risk of dying from severe manifestations of psychiatric illness. In some of these cases, patients are unwilling/unable to consent to ECT, and involuntary ECT is required. Such use of involuntary ECT varies substantially across European countries for unclear reasons. The aim of this study was to examine clinical and legal differences in this use of involuntary ECT across European countries. METHODS: A questionnaire based on a case vignette (a 55-year-old female inpatient with psychotic depression at imminent risk of dying from metabolic derangement because of refusal to eat and drink) was sent to an ECT practitioner in each of 31 European countries. RESULTS: We received responses from ECT practitioners in 18 countries. In 7 of these countries, involuntary ECT could be carried out without approval from others and/or involvement of the court system in the case described in the vignette. Practitioners in the remaining 11 countries responded that they either could not carry out involuntary ECT or would have to meet certain requirements before initiating involuntary ECT (e.g., approval from medical/ethics committee and second opinion from an independent psychiatrist). Notably, the rules regarding involuntary ECT differed for adults and minors (more restrictive for the latter) in 6 of the 18 countries. CONCLUSIONS: In many European countries, legislation precludes or delays the use of involuntary ECT. Harmonization of the legislation on involuntary ECT across European countries to allow for better access to this potentially life-saving treatment seems warranted.

Electroconvulsive Therapy Changes Immunological Markers in Patients With Major Depressive Disorder: A Scoping Review.

ABSTRACT: Major depressive disorder (MDD) is a highly prevalent and disabling condition. As such, understanding the causes of and treatment options for MDD is critical. Electroconvulsive therapy (ECT) remains the gold standard depression treatment, but the molecular mechanisms that underlie its effects are still largely unknown. One such explanation hinges on the immuno-inflammatory correlates of ECT treatment, given mounting evidence supporting the inflammatory hypothesis of depression. This review aims to provide an overview of the suggested immunomodulatory effects of ECT and the predictive value of immune biomarkers in relation to treatment outcomes and side effects. We conducted a preregistered, systematic literature search utilizing MEDLINE (PubMed), Embase (Elsevier), and PsycINFO (EBSCO) databases. We employed keywords related to MDD, ECT, gut microbiome, and the immune system. We only included human subjects research published between 1985 and January 13, 2021. Twenty-six unique studies were included in our analyses. Findings indicate a proinflammatory profile associated with MDD, with immune biomarkers exhibiting acute and chronic changes following ECT. Consistently, lower baseline interleukin 6 levels and higher C-reactive protein levels are correlated with a greater reduction in depressive symptoms following ECT. Furthermore, included studies emphasize the predictive value of peripheral immune changes, specifically interleukin 6 and tumor necrosis factor α, on cognitive outcomes following ECT. Given these results, further exploration of the potential roles of immunomodulatory effects on ECT treatment outcomes, as well as adverse cognitive side effects, is indicated.

The use of electroconvulsive therapy (ECT) en bloc in Denmark: a nationwide register-based study.

OBJECTIVE: Electroconvulsive therapy (ECT) en bloc is defined as ECT administered on 2-3 consecutive days. In Denmark, ECT en bloc is recommended for severe conditions such as catatonia, treatment-resistant mania/psychosis, or imminent risk of suicide. To our knowledge, there are no recent reports on the use of ECT en bloc in clinical practice. Here, we provide such a report. METHODS: We characterized the use of ECT en bloc in the period from 2006-2019 based on data from Danish national registers. Furthermore, we compared mortality rates between patients receiving ECT en bloc and patients receiving standard regimen ECT (not en bloc). RESULTS: We identified 2173 patients who received a total of 2734 ECT en bloc treatment courses in Denmark in the period from 2006 to 2019 (6% of the total number of ECT treatment courses). The use of ECT en bloc was stable over the study period (range: 138-196 patients per year). The most common treatment indications were unipolar depression (41%), psychotic disorder (23%), and bipolar disorder (20%). The vast majority (90%) received ECT en bloc voluntarily. The 1-year mortality rate ratio for ECT en bloc compared to standard regimen ECT was 1.42 (95%CI: 1.03-1.95). CONCLUSION: The use of ECT en bloc in Denmark is stable both in terms of the number of patients treated and treatment indications. In keeping with ECT en bloc being used for severe conditions, those receiving this treatment have a higher mortality rate compared to those receiving standard ECT, warranting careful monitoring during follow-up.

Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

OBJECTIVE: There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHOD: After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). RESULTS: With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. CONCLUSION: To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

Pharmacological interventions to diminish cognitive side effects of electroconvulsive therapy: A systematic review and meta-analysis.

OBJECTIVE: The authors conducted a systematic review and meta-analysis of pharmacological interventions to diminish cognitive side effects of ECT. METHODS: Electronic databases of Pubmed, PsycInfo, Embase and Scopus were searched from inception through 1 April, 2021, using terms for ECT (e.g. electroconvulsive therapy), cognitive outcome (e.g. cogni*) and pharmacological intervention (e.g. calcium channel blocker and general terms, like protein). Original studies with humans receiving ECT were included, which applied pharmacological interventions in comparison with placebo or no additive intervention to diminish cognitive side effects. Data quality was assessed using Risk of Bias and GRADE. Random-effects models were used. PROSPERO registration number was CRD42021212773. RESULTS: Qualitative synthesis (systematic review) showed 52 studies reporting sixteen pharmacological intervention-types. Quantitative synthesis (meta-analysis) included 26 studies (1387 patients) describing twelve pharmacological intervention-types. Low-quality evidence of efficacy was established for memantine (large effect size) and liothyronine (medium effect size). Very low-quality evidence shows effect of acetylcholine inhibitors, piracetam and melatonin in some cognitive domains. Evidence of no efficacy was revealed for ketamine (very low-quality), herbal preparations with anti-inflammatory properties (very low to low-quality) and opioid receptor agonists (low-quality). CONCLUSION: Memantine and liothyronine are promising for further research and future application. Quality of evidence was low because of differences in ECT techniques, study populations and cognitive measurements. These findings provide a guide for rational choices of potential pharmacological intervention research targets to decrease the burden of cognitive side effects of ECT. Future research should be more uniform in design and attempt to clarify pathophysiological mechanisms of cognitive side effects of ECT.

Electroconvulsive therapy for depression: 80 years of progress.

Electroconvulsive therapy is the most effective treatment for severe, psychotic or treatment-resistant depression. However, its effectiveness continues to be questioned, both in mainstream media and narratives within the scientific literature. In this analysis, we use an evidence-based approach to demonstrate the efficacy and safety of modern electroconvulsive therapy.

Electroconvulsive therapy and psychiatric readmission in major depressive disorder - A population-based register study.

OBJECTIVE: The primary aim was to determine whether electroconvulsive therapy (ECT) is associated with reduced risk of psychiatric readmission in major depressive disorder (MDD). METHODS: This study was based on data from multiple Swedish population-based registries. All adult patients admitted to any Swedish hospital for moderate-to-severe MDD between 2012 and 2018 were included. Participants were divided into two groups depending on whether they received ECT during inpatient care. Follow-up was set at 30 and 90 days from discharge. Data were analyzed using logistic regression, and matching was conducted. RESULTS: A total of 27,851 unique patients contributed to 41,916 admissions. ECT was used in 26.8% of admissions. In the main multivariate analysis, the risk of both 30- and 90-day readmission was lower in the ECT group than in the non-ECT group. In a matched sensitivity model, the results pointed in the same direction for readmission risk within 30 days, but statistical significance was not reached. ECT-treated subgroups with superior outcomes on readmission risk compared with non-ECT treatment were older, unemployed, married, or widowed patients, those treated with antipsychotics or benzodiazepines before admission, with psychotic features, prior psychiatric hospitalizations, or family history of suicide. However, in patients below 35 years of age, ECT was associated with increased readmission risk. CONCLUSION: This study suggests that ECT reduces the risk of psychiatric readmission in certain subgroups of patients with MDD. Since patients receiving ECT tend to be more difficult to treat, there is a risk of residual confounding.

Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Venlafaxine in Geriatric Depression: Phase 1 of the PRIDE Study.

OBJECTIVE: There is limited information regarding the tolerability of electroconvulsive therapy (ECT) combined with pharmacotherapy in elderly adults with major depressive disorder (MDD). Addressing this gap, we report acute neurocognitive outcomes from Phase 1 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHODS: Elderly adults (age ≥60) with MDD received an acute course of 6 times seizure threshold right unilateral ultrabrief pulse (RUL-UB) ECT. Venlafaxine was initiated during the first treatment week and continued throughout the study. A comprehensive neurocognitive battery was administered at baseline and 72 hours following the last ECT session. Statistical significance was defined as a two-sided p-value of less than 0.05. RESULTS: A total of 240 elderly adults were enrolled. Neurocognitive performance acutely declined post ECT on measures of psychomotor and verbal processing speed, autobiographical memory consistency, short-term verbal recall and recognition of learned words, phonemic fluency, and complex visual scanning/cognitive flexibility. The magnitude of change from baseline to end for most neurocognitive measures was modest. CONCLUSION: This is the first study to characterize the neurocognitive effects of combined RUL-UB ECT and venlafaxine in elderly adults with MDD and provides new evidence for the tolerability of RUL-UB ECT in an elderly sample. Of the cognitive domains assessed, only phonemic fluency, complex visual scanning, and cognitive flexibility qualitatively declined from low average to mildly impaired. While some acute changes in neurocognitive performance were statistically significant, the majority of the indices as based on the effect sizes remained relatively stable.

Clinical Practice Recommendations for Continuation and Maintenance Electroconvulsive Therapy for Depression: Outcomes From a Review of the Evidence and a Consensus Workshop Held in Australia in May 2017.

OBJECTIVES: Continuation or maintenance electroconvulsive therapy (ECT) is often provided as a strategy for post-ECT relapse prevention. However, the evidence has been insufficient until recently to produce clear consensus on what best practice maintenance ECT (mECT) should be like in a real world ECT clinical service. The aims of this article are to help fill this gap and to provide a comprehensive set of practical, clinically-based recommendations for ECT clinicians and services. METHODS: A workshop was held at the Royal Australian and New Zealand College of Psychiatry Congress in Adelaide on April 30, 2017. This workshop was hosted by the authors. After a presentation on the state of the evidence, the 30 participants were asked to work in small groups to develop consensus recommendations on different aspects of mECT. These were then collated into one comprehensive set of clinical recommendations for the practice of mECT. RESULTS: These best practice recommendations are set out below. CONCLUSIONS: These recommendations will assist ECT services and clinicians to provide best practice mECT according to currently available evidence.

Is Maintenance Electroconvulsive Therapy Always an Elective Procedure?: Weighing Medical Versus Psychiatric Risk.

Because of the severe nature of psychiatric illness, electroconvulsive therapy (ECT) is not always an "elective procedure." The pre-ECT medical evaluation, although important, should not be an impediment to timely ECT. We argue that an arbitrary regulation requiring new assessments every 30 days may be unduly burdensome and unnecessary. The small medical risk of treatment should be weighed against the potential psychiatric risk (including suicide) of delayed treatment.

Extreme variability in succinylcholine dose for muscle relaxation in electroconvulsive therapy.

OBJECTIVES: To determine what dose of succinylcholine falls outside the range of 2 SD above or below the mean optimal dose of 0.9 mg/kg used for electroconvulsive therapy (ECT). METHODS: In this retrospective chart review, for all patients who received ECT at our institution within the 5-year study period, the initial dose of succinylcholine in milligrams per kilogram was compared with subsequent doses after adjustments were made for individual patient responses. Mean and SD were calculated using the dose of succinylcholine, once the optimal dose for each patient had been determined, based on clinical response. RESULTS: Five hundred patients treated during the 5-year period met inclusion criteria, 180 (36%) of whom required an adjustment of the succinylcholine dosing either above (119 patients) or below (61 patients) the 0.9 mg/kg standard after their first treatment. CONCLUSIONS: In those patients who required an adjustment of 2 SD either above or below the mean dose of succinylcholine (29 patients, 5.8%), adequate neuromuscular blockade was only achieved with either an increased dose of up to 2.10 mg/kg or a decreased dose as low as 0.29 mg/kg.