Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

The genetics of severe depression.

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium.

National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

Low-Frequency Right Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression After Traumatic Brain Injury: A Randomized Sham-Controlled Pilot Study.

OBJECTIVE: Major depression is the most common psychiatric sequela of traumatic brain injury (TBI), but effective treatment continues to be a challenge, with few studies providing guidance. METHODS: In a pilot study, the authors evaluated the effect size of low-frequency right-sided (LFR) repetitive transcranial magnetic stimulation (rTMS), compared with sham treatment, over the right dorsolateral prefrontal cortex (DLPFC) in patients (N=30) with TBI depression and co-occurring neuropsychiatric symptoms, including suicidal thoughts, anxiety, posttraumatic stress disorder, sleep disturbance, behavioral problems, and cognitive dysfunction. Exploratory analyses of diffusion tensor imaging pre- and postintervention were performed to determine the effect size of LFR rTMS on white matter integrity. RESULTS: Small (Hedge's g=0.19) and highly variable effects of LRF rTMS over right DLPFC in TBI depression were observed. Similarly, the effect of LFR rTMS for treatment of comorbid neuropsychiatric symptoms varied from small to moderate. CONCLUSIONS: These findings suggest that the observed effects of LFR rTMS over the right DLPFC in TBI depression and co-occurring neuropsychiatric symptoms are small, at best, and, preliminarily, that low-frequency right DLPFC stimulation has limited potential in this patient population. However, studies employing different rTMS parameters (e.g., type, location, frequency, duration) or other participant characteristics (e.g., TBI severity, chronicity, comorbidity, concurrent treatment) may potentially yield different responses.

Defense Automated Neurobehavioral Assessment Accurately Measures Cognition in Patients Undergoing Electroconvulsive Therapy for Major Depressive Disorder.

OBJECTIVES: The Defense Automated Neurobehavioral Assessment (DANA) is an electronic cognitive test battery. The present study compares DANA to the standard Mini-Mental State Examination (MMSE) in subjects undergoing electroconvulsive therapy for the treatment of major depressive disorder. METHODS: Seventeen inpatient subjects in the Johns Hopkins Hospital Department of Psychiatry were administered longitudinal paired DANA and MMSE tests (7.6 ± 4.1 per patient) from January 10, 2014 to September 26, 2014. Regression analyses were conducted (with or without MMSE scores of 30) to study the impact of the MMSE upper limit, and within-subject regression analyses were conducted to compare MMSE and DANA scores over time. RESULTS: Statistically significant relationships were measured between DANA and MMSE scores. Relationships strengthened when MMSE scores of 30 were omitted from analyses, demonstrating a ceiling effect of the MMSE. Within-subject analyses revealed relationships between MMSE and DANA scores over the duration of the inpatient stay. CONCLUSIONS: Defense Automated Neurobehavioral Assessment is an electronic, mobile, repeatable, sensitive, and valid method of measuring cognition over time in depressed patients undergoing electroconvulsive therapy treatment. Automation of the DANA allows for more frequent cognitive testing in a busy clinical setting and enhances cognitive assessment sensitivity with a timed component to each test.

Key updates in the clinical application of electroconvulsive therapy.

ECT is the oldest and most effective therapy available for the treatment of severe major depression. It is highly effective in individuals with treatment resistance and when a rapid response is required. However, ECT is associated with memory impairment that is the most concerning side-effect of the treatment, substantially contributing to the controversy and stigmatization surrounding this highly effective treatment. There is overwhelming evidence for the efficacy and safety of an acute course of ECT for the treatment of a severe major depressive episode, as reflected by the recent FDA advisory panel recommendation to reclassify ECT devices from Class III to the lower risk category Class II. However, its application for other indications remains controversial, despite strong evidence to the contrary. This article reviews the indication of ECT for major depression, as well as for other conditions, including catatonia, mania, and acute episodes of schizophrenia. This study also reviews the growing evidence supporting the use of maintenance ECT to prevent relapse after an acute successful course of treatment. Although ECT is administered uncommonly to patients under the age of 18, the evidence supporting its use is also reviewed in this patient population. Finally, memory loss associated with ECT and efforts at more effectively monitoring and reducing it are reviewed.

A review of repetitive transcranial magnetic stimulation for adolescents with treatment-resistant depression.

This review examines the efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) as a treatment for treatment-resistant depression in adolescents. A systematic review of six databases was conducted. Ten multi-subject trials, all uncontrolled, and five case reports met inclusion criteria. Twelve studies focused on treatment efficacy, whereas three studies focused exclusively on adverse events. All efficacy studies focused on adolescents only; 10 of these studies indicated that rTMS may demonstrate some benefit. Improvement within 2-8 weeks was reported in most studies, with a few studies indicating potential long-term benefits. A variety of adverse events occurred including scalp pain, which was the most common, as well as seizures. Controlled studies of rTMS are warranted to further examine whether this treatment is a potential option for adolescents with treatment-resistant depression.

Treatment of Severe Self-Injurious Behavior in Autism Spectrum Disorder by Neuromodulation.

An increasing number of case reports and series document the safe and effective use of electroconvulsive therapy (ECT) in children, adolescents, and young adults with autism spectrum disorder who engage in severe, intractable, repetitive self-injurious behavior (SIB) without environmental or operant function. Although the treatment is very effective for such patients, they typically remain highly dependent on frequent maintenance ECT (M-ECT) to maintain suppression of the SIB achieved during the acute course. Some patients receive M-ECT as frequently as once every 5 days. Such a regimen is quite burdensome for the patient and the patient's family, and the long-term effects of such regimens, starting as early as childhood, are unknown. In this review, we explore the expanding literature supporting the use of ECT for suppressing severe SIB associated with autism spectrum disorder. We also focus on the possible development of alternate nonconvulsive focal forms of brain stimulation, which might replace frequent M-ECT or reduce how frequently a patient needs to receive it. Although there are scarce clinical data currently available supporting these latter treatments, future studies are clearly indicated.

Transcranial magnetic stimulation: A potential new treatment for depression associated with traumatic brain injury.

BACKGROUND: Each year, more than 1.7 million Americans suffer a traumatic brain injury (TBI) and the lifetime prevalence of major depressive disorder following TBI is between 25-50%. There are no validated established strategies to treat TBI depression. Repetitive transcranial magnetic stimulation (rTMS) is a novel putative treatment option for post-TBI depression, which, compared with standard pharmacological agents, may provide a more targeted treatment with fewer side-effects. However, TBI is associated with an increased risk of both early and late spontaneous seizures, a significant consideration in evaluating rTMS as a potential treatment for TBI depression. Whilst the risk of seizure from rTMS is low, underlying neuropathology may somewhat increase that risk. REVIEW: This review focuses on the safety aspects of rTMS in TBI patients. The authors review why low frequency rTMS might be less likely to trigger a seizure than high frequency rTMS and propose low frequency rTMS as a safer option in TBI patients. Because there is little data on the safety of rTMS in TBI, the authors also review the safety of rTMS in patients with other brain pathology. CONCLUSION: It is concluded that pilot safety and tolerability studies should be first conducted in persons with TBI and neuropsychiatric comorbidities. These results could be used to help design larger randomized controlled trials.

Predictors of electroconvulsive therapy postictal delirium.

BACKGROUND: Postictal delirium is a common adverse effect of electroconvulsive therapy (ECT) and can be dangerous to both patient and staff caring for them in the postanesthesia care unit. However, little is known about predictors of postictal delirium. OBJECTIVES: The aim of this study was to identify predictors of postictal delirium. We hypothesized that both patient and ECT treatment variables might influence the likelihood of postictal delirium. METHODS: We prospectively monitored postictal delirium in the postanesthesia care unit using the Confusion Assessment Method for the Intensive Care Unit after the first ECT treatment of 96 consecutive patients. Patient and treatment variables were extracted retrospectively by chart review. A multiple logistic regression model was developed to assess the effect of these variables on the likelihood of developing delirium. RESULTS: Seizure length was found to be a statistically significant predictor of postictal delirium after adjusting for other covariates (p = 0.003). No other variables were predictive. CONCLUSION: A long ECT seizure increases the likelihood of delirium in the postanesthesia care unit at the first treatment. This finding suggests that postanesthesia care unit staff may benefit from knowledge about seizure length for predicting postictal delirium and anticipating the best management of post-ECT patients.

Stability of intraocular pressure after retinal reattachment surgery during electroconvulsive therapy for intractable self-injury in a 12-year-old autistic boy.

We present a 12-year-old autistic boy who underwent electroconvulsive therapy (ECT) for intractable self-injury toward his head and eyes in the context of acute bilateral retinal detachment and reparative surgery. The patient received 3 ECTs before retinal reattachment surgery, and resumed ECT 2 weeks postoperatively. Bilateral intraocular pressures were monitored before and after the first 7 ECTs and intermittently after ECT for 10 months of maintenance ECT. There was no evidence of sustained intraocular pressure elevation or instability. This report supports the safety of ECT for repetitive self-injury in youth before and after emergent ophthalmologic surgery for trauma-related injury.

Role of medial prefrontal cortex Narp in the extinction of morphine conditioned place preference.

Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus (AAV) expressing wild-type (WT) Narp into the mPFC of Narp KO mice rescued the extinction and the injection of AAV expressing a dominant negative form of Narp (NarpN) into the mPFC of WT mice impaired the extinction of morphine CPP. These findings suggest that Narp in the mPFC mediates the extinction of morphine CPP.

Fast depressive symptoms improvement in bipolar I disorder after Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT): A two-site feasibility and safety open-label trial.

BACKGROUND: Although there are a few first-line treatment options for bipolar depression, none are rapid-acting. A new rTMS protocol, Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT®), has been shown to have a rapid antidepressant effect in major depressive disorder (MDD). We examined the preliminary safety, tolerability, and efficacy of SAINT for the treatment of depression in a small sample of persons with treatment-resistant bipolar I disorder. METHODS: Participants with treatment-resistant bipolar I disorder currently experiencing moderate to severe depression were treated with open-label SAINT. Resting-state functional MRI (fMRI) was used to generate individualized treatment targets for each participant based on the region of the left dorsolateral prefrontal cortex most anticorrelated with the subgenual anterior cingulate cortex. Participants were treated with 10 iTBS sessions daily, with 50-min intersession intervals, for up to 5 consecutive days. The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to immediate follow-up after treatment. RESULTS: We treated 10 participants and found a mean reduction of 16.9 in MADRS scores, with a 50 % response rate and 40 % remission rate immediately following treatment. 60 % of participants met remission criteria within the 1-month period following treatment. No serious adverse events, manic episodes, or cognitive side effects were observed. LIMITATIONS: Our study has a limited sample size and larger samples are needed to confirm safety and efficacy. CONCLUSIONS: SAINT has shown preliminary feasibility, safety, tolerability, and efficacy in treating treatment-resistant bipolar I depression. Double-blinded sham-controlled trials with larger samples are needed to confirm safety and efficacy.

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. Objective: To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. Design, Setting, and Participants: This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Exposures: Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Main Outcomes and Measures: Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Results: Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. Conclusions and Relevance: In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

Neuronal activity-regulated pentraxin expressed in medial prefrontal cortex neurons is not necessary for extinction of heroin self-administration.

The medial prefrontal cortex (mPFC) plays a key role in extinction learning. Previously, we found that expression of a neuronal activity-regulated pentraxin (Narp) dominant-negative construct in the mPFC of mice blocked extinction of morphine-conditioned place preference. To further investigate the role of mPFC Narp in the extinction of drug seeking, we tested whether mPFC Narp is necessary for the extinction of heroin self-administration in rats. Specifically, we injected an adeno-associated viral vector expressing a dominant-negative form of Narp (NarpN) into the infralimbic region of the mPFC of rats and compared lever presses during extinction to those of rats injected with a control virus. In contrast to our previous study, we found that injection of NarpN did not affect extinction of heroin self-administration. Our findings suggest that mPFC Narp is necessary for extinction of opiate seeking in the Pavlovian-conditioned place preference paradigm but not in the operant paradigm of drug self-administration.

A rational insurance coverage policy for repetitive transcranial magnetic stimulation for major depression.

Although most health insurance plans do not cover repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depression, coverage is increasing, with approval often granted on a case-by-case basis. Accordingly, it is important for physicians who are advocating for coverage on behalf of their patients to provide cogent arguments based on published data. Most patients presenting for rTMS have medication resistance that is beyond the Food and Drug Administration-approved indication of one failed but adequate trial of an antidepressant medication. However, recent naturalistic studies lend support to the proposition that rTMS is efficacious for more medication-resistant patients.

ECT treatment outcomes following performance improvement changes.

Differences in electroconvulsive therapy (ECT) outcomes were explored following changes in ECT administration at our institution. Two changes were introduced: (a) switching the anesthetic agent from propofol to methohexital, and (b) using a more aggressive ECT charge dosing regimen for right unilateral (RUL) electrode placement. Length of stay (LOS) and number of treatments administered per patient were monitored. A retrospective analysis was performed of two inpatient groups treated on our Mood Disorders Unit: those who underwent ECT in the 12 months prior to the changes (n = 40) and those who underwent treatment in the 12 months after the changes (n = 38). Compared with patients receiving ECT with RUL placement prior to the changes, patients who received RUL ECT after the changes had a significantly shorter inpatient LOS (27.4 versus 18 days, p = 0.028). Treatment efficacy monitored by the Montgomery Asberg Depression Rating Scale was not impacted. The change in anesthetic agent and charge dosing each accounted for 11% of the variance in LOS among patients receiving RUL ECT. The implemented changes in ECT administration positively impacted outcome for patients receiving treatment with RUL electrode placement.