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 After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients.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.).

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.

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.

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.

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.

Flumazenil pretreatment in benzodiazepine-free patients: a novel method for managing declining ECT seizure quality.

OBJECTIVE: Seizure threshold increases with successive electroconvulsive therapy (ECT) treatments, which can be especially problematic when treating older patients who have higher seizure thresholds at baseline because ECT devices are limited by the amount of charge that can be delivered. CASE REPORTS: We present a case series of 3 older patients who had long ECT courses that were complicated by inability to generate seizures, poor quality seizures, and inadequate clinical response despite established measures to lower seizure threshold including prehydration, hyperventilation, and minimizing methohexital dose using remifentanil. As preclinical studies show electroconvulsive seizure increases diazepam binding, we hypothesized that a contributor to declining seizure quality and inadequate ECT responsiveness in these individuals was enhanced benzodiazepine receptor function, although none of the 3 patients were taking benzodiazepines or any other anticonvulsant medication. Accordingly, we pretreated patients with flumazenil, a competitive inhibitor at the benzodiazepine-binding site, and observed improvement in seizure quality and clinical response. CONCLUSION: Flumazenil pretreatment of elderly ECT patients with declining seizure quality and inadequate clinical response in the setting of repeated treatments may represent a novel strategy for managing such patients. A clinical trial would be required to test this hypothesis.

Asystole in ultrabrief pulse electroconvulsive therapy.

OBJECTIVES: Ultrabrief (UB) pulse electroconvulsive therapy (ECT) has been gaining popularity in recent years because of its improved cognitive adverse effect profile compared with treatments triggered by brief pulses. When delivered at maximal charge, UB pulses are administered for 8 seconds. Because electrical stimulation triggers a parasympathetic surge and transient asystole, we checked whether UB pulses delivered for 8 seconds were associated with prolonged cardiac pause compared with maximal charge delivered for 4 seconds with brief pulses. METHODS: This is a retrospective study of cardiac pause length of all patients undergoing ECT treatment at The Johns Hopkins Hospital during 1 year. RESULTS: Electrocardiac pause length for patients undergoing ECT with right unilateral placement at maximal charge was not affected by pulse width. However, we did find cardiac pause length to be sensitive to 2- versus 4-second duration stimuli using brief pulses (P < 0.0001). CONCLUSIONS: Notwithstanding the clear limitations of small sample size and retrospective design, we found that right unilateral ECT was not affected by pulse width when maximal charge was delivered.

Decreasing adverse outcomes of unmodified electroconvulsive therapy: suggestions and possibilities.

Electroconvulsive therapy (ECT) is far and away the most effective treatment for depression and quite effective for a range of other psychiatric conditions that are unresponsive to medication. Electroconvulsive therapy in the developed world has been administered with anesthesia, muscle relaxants, and ventilation since the mid-1950s following 20 years of unmodified treatment. However, in much of the developing world, ECT continues to be administered unmodified because of lack of resources. We review the efficacy of unmodified compared with modified treatment. We also review the potential drawbacks of unmodified treatment including fear and anxiety, worse postictal confusion, fracture risk, and the negative effects of unmodified treatment on how ECT is perceived in the general community. Finally, we consider potential solutions in developing countries to minimize adverse outcomes of unmodified treatment by pretreating patients either with low-dose benzodiazepines or sedating, but not anesthetizing, dosages of anesthetic agents. Randomized controlled trials are necessary before either of these options could be considered an acceptable alternative to completely unmodified treatment when modified treatment is unavailable.

Monoamine oxidase A regulates antisocial personality in whites with no history of physical abuse.

OBJECTIVE: Preclinical and human family studies clearly link monoamine oxidase A (MAOA) to aggression and antisocial personality (ASP). The 30-base pair variable number tandem repeat in the MAOA promoter regulates MAOA levels, but its effects on ASP in humans are unclear. METHODS: We evaluated the association of the variable number tandem repeat of the MAOA promoter with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ASP disorder (ASPD) traits in a community sample of 435 participants from the Hopkins Epidemiology of Personality Disorders Study. RESULTS: We did not find an association between the activity of the MAOA allele and ASPD traits; however, among whites, when subjects with a history of childhood physical abuse were excluded, the remaining subjects with low-activity alleles had ASPD trait counts that were 41% greater than those with high-activity alleles (P < .05). CONCLUSION: The high-activity MAOA allele is protective against ASP among whites with no history of physical abuse, lending support to a link between MAOA expression and antisocial behavior.

Localized disruption of Narp in medial prefrontal cortex blocks reinforcer devaluation performance.

Neuronal activity regulated pentraxin (Narp) is a secreted protein that regulates α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPAR) aggregation and synaptogenesis. Mapping of Narp-positive neurons in brain has revealed it is prominently expressed in several limbic system projection pathways. Consistent with this localization pattern, Narp knockout mice show deficits in using the current value of a reinforcer to guide behavior, a critical function of the limbic system. To help assess whether this behavioral deficit is due to impairment of synaptogenesis during development or in modulating synaptic signaling in the mature brain, we have used a dominant negative Narp viral construct which blocks trafficking of endogenous Narp to axons. Focal injection of this viral construct into the medial prefrontal cortex (mPFC) of adult mice, a region containing Narp-positive projection neurons, blocked reinforcer devaluation. Thus, these results indicate that Narp released from mPFC neurons plays a key role in mediating synaptic changes underlying instrumental reinforcer devaluation.