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 After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients.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

A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function.

Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress.

ElectroConvulsive therapy Cognitive Assessment (ECCA) tool: A new instrument to monitor cognitive function in patients undergoing ECT.

BACKGROUND: Electroconvulsive therapy (ECT) is a well-established treatment for severe depression but may result in adverse cognitive effects. Available cognitive screening instruments are nonspecific to the cognitive deficits associated with ECT. An ECT-cognitive assessment tool which can be easily administered was developed and validated in a clinical setting. METHODS: One hundred and thirty-six participants were enrolled. The ElectroConvulsive therapy Cognitive Assessment (ECCA) and the Montreal Cognitive Assessment (MoCA) were administered prospectively to 55 participants with major depressive disorder (MDD) undergoing ECT at three time points: pre-treatment, before the sixth treatment and one-week post-treatment. The psychometric properties of the total and domain scores were evaluated at all three time points. Forty demographically comparable participants with MDD who did not receive ECT, and 41 healthy, age-matched controls were evaluated at a single time point. RESULTS: ECCA and MoCA scores were not statistically different at baseline. Prior to the sixth and final ECT session, total ECCA scores were significantly lower than the MoCA total scores. The ECCA domains of subjective memory, informant-assessed memory, attention, autobiographical memory and delayed verbal recall were significantly lower post-ECT compared to pre-ECT. LIMITATIONS: The ECCA was compared only to the MoCA rather than to a more comprehensive neuropsychological testing. This limitation reflected the real-life clinical burden of performing full neuropsychological testing at three time points during the treatment course. CONCLUSIONS: The ECCA is a brief, reliable, bedside cognitive screening assessment tool that may be useful to monitor cognitive function in patients treated with ECT. The test can be downloaded from fuquacenter.org/ecca.

Non-suicidal self-injury and electroconvulsive therapy: Outcomes in adolescent and young adult populations.

BACKGROUND: Electroconvulsive (ECT) therapy is a highly effective treatment for severe depression. Although the clear majority of patients respond to ECT, not all do, and we still lack good predictors for ECT outcome, especially in adolescents and young adults. One clinical variable that has been associated with reduced likelihood of ECT antidepressant response in adults is comorbid borderline personality disorder. As self-injurious behavior is often a feature of borderline personality disorder, we hypothesized that adolescent and young adult patients with a history of non-suicidal self-injury (NSSI), who were being treated for major depression with ECT, would have a poorer response than patients without such a history. METHODS: We conducted a retrospective chart review of 48 patients treated with ECT for depression at The Johns Hopkins Hospital between the ages of 14 and 25. RESULTS: Initial analyses showed that the presence of NSSI was not associated with ECT outcomes. However, sub-group analyses suggested that it was associated with response to ECT and overall remission among female patients. Specifically, the results suggested that in adolescent and young adult female ECT patients, the presence of NSSI was associated with lower odds of response (OR: 0.04; 95% CI: 0.0004, 0.81, p = 0.03) and remission (OR: 0.09; 95% CI: 0.0000, 0.81, p = 0.03), and a greater mean number of treatments (5.83; 95% CI: 0.27, 11.39, p = 0.04) compared with patients without NSSI. CONCLUSIONS: Clearly, the finding that NSSI may be associated with poorer ECT outcomes among female patients needs to be replicated. Nonetheless, our data suggest caution when considering an adolescent or young adult woman for a course of ECT.

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.

Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression.

OBJECTIVE: To provide expert recommendations for the safe and effective application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD). PARTICIPANTS: Participants included a group of 17 expert clinicians and researchers with expertise in the clinical application of rTMS, representing both the National Network of Depression Centers (NNDC) rTMS Task Group and the American Psychiatric Association Council on Research (APA CoR) Task Force on Novel Biomarkers and Treatments. EVIDENCE: The consensus statement is based on a review of extensive literature from 2 databases (OvidSP MEDLINE and PsycINFO) searched from 1990 through 2016. The search terms included variants of major depressive disorder and transcranial magnetic stimulation. The results were limited to articles written in English that focused on adult populations. Of the approximately 1,500 retrieved studies, a total of 118 publications were included in the consensus statement and were supplemented with expert opinion to achieve consensus recommendations on key issues surrounding the administration of rTMS for MDD in clinical practice settings. CONSENSUS PROCESS: In cases in which the research evidence was equivocal or unclear, a consensus decision on how rTMS should be administered was reached by the authors of this article and is denoted in the article as "expert opinion." CONCLUSIONS: Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy. These consensus recommendations, developed by the NNDC rTMS Task Group and APA CoR Task Force on Novel Biomarkers and Treatments, provide comprehensive information for the safe and effective clinical application of rTMS in the treatment of MDD.

Narp Mediates Antidepressant-Like Effects of Electroconvulsive Seizures.

Growing recognition of persistent cognitive defects associated with electroconvulsive therapy (ECT), a highly effective and commonly used antidepressant treatment, has spurred interest in identifying its mechanism of action to guide development of safer treatment options. However, as repeated seizure activity elicits a bewildering array of electrophysiological and biochemical effects, this goal has remained elusive. We have examined whether deletion of Narp, an immediate early gene induced by electroconvulsive seizures (ECS), blocks its antidepressant efficacy. Based on multiple measures, we infer that Narp knockout mice undergo normal seizure activity in this paradigm, yet fail to display antidepressant-like behavioral effects of ECS. Although Narp deletion does not suppress ECS-induced proliferation in the dentate gyrus, it blocks dendritic outgrowth of immature granule cell neurons in the dentate molecular layer induced by ECS. Taken together, these findings indicate that Narp contributes to the antidepressant action of ECT and implicate the ability of ECS to induce dendritic arborization of differentiating granule cells as a relevant step in eliciting this response.

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.

A naturalistic, multi-site study of repetitive transcranial magnetic stimulation therapy for depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) was approved in 2008 in the United States, and there are relatively few studies describing its use in regular clinical practice since approval. METHODS: From April 2011 to October 2014, ten sites within the National Network of Depression Centers (NNDC) provided data on 62 evaluable patients with a depressive episode. Treatment was determined naturalistically. Response was assessed by the Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR) as the primary outcome, and the Patient Health Questionnaire-9 (PHQ-9) and the clinician-rated Clinical Global Impression (CGI) as secondary depression measures. RESULTS: Enrolled patients exhibited significant treatment resistance, with 70.2% reporting more than 4 prior depressive episodes. Most patients received treatment with standard parameters (10Hz over the left dorsolateral prefrontal cortex), although 22.6% of the patients received 1 or 5Hz stimulation at some point. Over 6 weeks of treatment, response and remission rates were 29.4% and 5.9%, respectively, for the QIDS-SR; 39.2% and 15.7%, respectively, for the PHQ-9; and 50.9% and 17.9%, respectively, for the CGI. Moderator analyses revealed no effect of prior depressive episodes, history of ECT or gender, although early life stress predicted a better response to rTMS therapy. LIMITATIONS: The study was an open-label, registry trial, with relatively coarse clinical data, reflecting practice only in academic, depression-specialty centers. Because of the relatively small size and heterogeneity of the sample, type 2 errors are possible and positive findings are in need of replication. CONCLUSION: rTMS demonstrates effectiveness in clinical practice within the NNDC, although remission rates appear slightly lower in comparison with other recent naturalistic studies.

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.

High-Frequency Stimulation at the Subthalamic Nucleus Suppresses Excessive Self-Grooming in Autism-Like Mouse Models.

Approximately one quarter of individuals with an autism spectrum disorder (ASD) display self-injurious behavior (SIB) ranging from head banging to self-directed biting and punching. Sometimes, these behaviors are extreme and unresponsive to pharmacological and behavioral therapies. We have found electroconvulsive therapy (ECT) can produce life-changing results, with more than 90% suppression of SIB frequency. However, these patients typically require frequent maintenance ECT (mECT), as often as every 5 days, to sustain the improvement gained during the acute course. Long-term consequences of such frequent mECT started as early as childhood in some cases are unknown. Accordingly, there is a need for alternative forms of chronic stimulation for these patients. To explore the feasibility of deep brain stimulation (DBS) for intractable SIB seen in some patients with an ASD, we utilized two genetically distinct mouse models demonstrating excessive self-grooming, namely the Viaat-Mecp2(-/y) and Shank3B(-/-) lines, and administered high-frequency stimulation (HFS) via implanted electrodes at the subthalamic nucleus (STN-HFS). We found that STN-HFS significantly suppressed excessive self-grooming in both genetic lines. Suppression occurs both acutely when stimulation is switched on, and persists for several days after HFS is stopped. This effect was not explained by a change in locomotor activity, which was unaffected by STN-HFS. Likewise, social interaction deficits were not corrected by STN-HFS. Our data show STN-HFS suppresses excessive self-grooming in two autism-like mouse models, raising the possibility DBS might be used to treat intractable SIB associated with ASDs. Further studies are required to explore the circuitry engaged by STN-HFS, as well as other potential stimulation sites. Such studies might also yield clues about pathways, which could be modulated by non-invasive stimulatory techniques.