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.

Postoperative Maintenance of Sagittal Plane Positioning of the First Metatarsophalangeal Joint After Arthrodesis with an Isolated Dorsal Plate Construct: A Retrospective Review of 43 Feet.

BACKGROUND: First metatarsophalangeal joint arthrodesis with isolated dorsal plating without a lag screw and without a compressive mechanism incorporated into the plate is not well studied. Although surface area for bony fusion is increased, there is concern for lower fusion rates and progressive loss of sagittal plane positioning. We present fusion rates and progressive sagittal plane deviation with isolated dorsal plate fixation. METHODS: A retrospective review was performed of 41 patients (43 feet) who underwent first metatarsophalangeal joint arthrodesis with isolated dorsal plate fixation. Patients were excluded if another form of fixation was used, if there was a compressive feature to the dorsal plate, or if a lag screw was used. Preoperative, immediate postoperative, and final postoperative radiographs were reviewed to assess radiographic alignment and fusion about the first metatarsophalangeal joint. Specific attention was placed on hallux dorsiflexion in relation to the first metatarsal. Statistical significance was set at P ≤ .05 a priori. RESULTS: Patients were followed for an average of 55.7 weeks. Overall union rate was 97.62%. The average time to union was 42.55 days. Reoperation rate was 4.65%, with one patient requiring revisional arthrodesis with a lag screw construct. Hallux abduction and first-second intermetatarsal angle correction reached significance (P < .00001). Hallux dorsiflexion increased by 1.05° between initial postoperative and final postoperative radiographs (P = .542). CONCLUSIONS: Although fusion rates and progressive loss of sagittal plane position have been concerns for first metatarsophalangeal joint arthrodesis with an isolated dorsal plate construct, these results suggest this to be a stable construct without loss of positioning over time.

Development of a Communication Skills Training to Enhance Effective Team Communication in Oncology.

INTRODUCTION: Effective communication among members of health care teams is essential to provide quality and patient-centered care, yet many people identify this as a challenge. We developed, implemented, and conducted a preliminary evaluation of a training to enhance communication within oncology teams. METHODS: This training identifies key strategies, communication skills, and process tasks recommended to achieve the goal of using a collaborative approach to navigate communication interactions across members of the hospital team to enhance patient care outcomes and increase team effectiveness. Forty-six advanced practice providers (APPs) participated and completed an evaluation of the module. RESULTS: Eighty-three percent of participants identified as female and 61% were White. Eighty-three percent of participants were nurse practitioners and 17% were physician assistants. The module was highly rated. Participants responded that they were satisfied ("agree" or "strongly agree") on 16 of 17 evaluation items (80% or higher). DISCUSSION: APPs were satisfied with the course and found many aspects useful in learning and practicing skills to improve their communication with other team members to enhance their care of patients. Training with this module and other communication approaches are needed for health care professionals of all types to encourage more consistent and meaningful communication with their colleagues to improve patient care.

Clinical Outcomes of Magnetic Seizure Therapy vs Electroconvulsive Therapy for Major Depressive Episode: A Randomized Clinical Trial.

Importance: Electroconvulsive therapy (ECT) is highly effective and rapid in treating depression, but it carries a risk of significant cognitive adverse effects. Magnetic seizure therapy (MST), an investigational antidepressant treatment, may maintain the robust antidepressant efficacy of ECT while substantially reducing adverse effects due to its enhanced focality and weaker stimulation strength; however, previous clinical trials of MST were limited by small sample sizes. Objective: To compare the antidepressant efficacy of MST vs ultrabrief pulse right unilateral (RUL) ECT. Design, Setting, and Participants: A between-participants, double-blinded, randomized clinical trial was conducted at 3 academic hospitals from June 2007 to August 2012. Adults aged 18 to 90 years who were referred for treatment with ECT, had a major depressive episode in the context of major depressive disorder or bipolar disorder, and had a baseline 24-item Hamilton Depression Rating Scale (HDRS-24) total score of 18 or higher were included. Participants were randomly assigned 1:1 to treatment with MST or ultrabrief pulse RUL ECT. After the treatment course, patients were naturalistically followed up for up to 6 months to examine the durability of clinical effects. Interventions: Treatment with MST, applied at 100 Hz at 100% of the maximum device power for 10 seconds, or ultrabrief pulse RUL ECT, applied at 6 times seizure threshold. Main Outcomes and Measures: The primary outcome was change from baseline in HDRS-24 total score, with patients followed up for up to 6 months. A reduction of at least 50% in the HDRS-24 score indicated response, and at least a 60% decrease in the HDRS-24 score and a total score of 8 or less indicated remission. Results: Of the 73 participants (41 [56.2%] female; mean [SD] age, 48 [14.1] years), 35 were randomized to MST and 38 to ECT. Among them, 53 (72.6%) were classified as completers (29 in the MST group and 24 in the ECT group). Both MST and ECT demonstrated clinically meaningful antidepressant effects. In the intent-to-treat sample, 18 participants (51.4%) in the MST group and 16 (42.1%) in the ECT group met response criteria; 13 (37.1%) in the MST group and 10 (26.3%) in the ECT group met remission criteria. Among completers, 17 of 29 (58.6%) in the MST group and 15 of 24 (62.5%) in the ECT group met response criteria; 13 of 29 (44.8%) in the MST group and 10 of 24 (41.7%) in the ECT group met remission criteria. There was no significant difference between MST and ECT for either response or remission rates. However, the mean (SD) number of treatments needed to achieve remission was 9.0 (3.1) with MST and 6.7 (3.3) with ECT, a difference of 2.3 treatments (t71.0 = 3.1; P = .003). Both MST and ECT showed a sustained benefit over a 6-month follow-up period, again with no significant difference between them. Compared with MST, ECT had significantly longer time to orientation after treatment (threshold level: F1,56 = 10.0; P = .003) and greater severity of subjective adverse effects, particularly in the physical and cognitive domains. Conclusions and Relevance: This randomized clinical trial found that the efficacy of MST was indistinguishable from that of ultrabrief pulse RUL ECT, the safest form of ECT currently available. These results support the continued development of MST and provide evidence for advantages relative to state-of-the-art ECT. Trial Registration: ClinicalTrials.gov Identifier: NCT00488748.

Using latent profile analyses to classify subjects with anhedonia based on reward-related measures obtained in the FAST-MAS study.

BACKGROUND: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments. METHODS: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures. RESULTS: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures. LIMITATIONS: The main limitations include the small sample size and exploratory nature of analyses. CONCLUSIONS: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity.

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.

General and Unique Communication Skills Challenges for Advanced Practice Providers: A Mixed-Methods Study.

AIMS: Advanced practice providers are a rapidly growing sector of the health-care field. Despite their relatively new place in the medical establishment, these providers are held to high standards of education, practice, and communication skills. However, the communication needs of these practitioners are somewhat different than those of nurses or physicians. These skills are even more necessary in specialized fields where providers frequently are involved in discussions of prognosis, goals of care, and end of life. DESIGN: This was a mixed-methods study. METHODS: We completed a needs assessment of communication skills for advanced practice providers at a large cancer center in the northeastern United States from June to July 2017. RESULTS: Participants were confident in their skills across several areas of communication, but also endorsed the need for communication skills training, particularly for challenging interactions with patients and families. Advanced practice providers described many challenges similar to those descried by other health-care providers, including general communication skills problems, navigating team dynamics, and goals-of-care planning. However, participants also endorsed communication skills needs specific to their field, including certain patient-centered challenges, perceived/real limitations of their role, serving as the "middleman," and understanding the advanced practice provider's role. CONCLUSION: Given the general and unique communication challenges advanced practice providers in oncology face, we conclude with recommendations for further institutional and educational changes to better address these needs.

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.

Peripheral Nerve Stimulation for Facial Pain Using Wireless Devices.

Since its original introduction several decades ago, peripheral nerve stimulation (PNS) of the craniofacial region has been traditionally performed using devices intended for spinal cord stimulation applications with inevitably high rate of technical challenges and procedural complications. The lower invasiveness of recently developed wireless neurostimulation systems makes them much better suited for craniofacial applications. Here, we discuss the preliminary clinical data from several published reports and the ongoing multicenter prospective study of wireless PNS in the craniofacial region. Advances in wireless transmission of electrical signals may make wireless neurostimulation even more attractive in the future. Since most of the evidence supporting PNS for facial pain comes from small subsets of the population, case series and case reports, there will need to be larger, randomized controlled trials with cost efficacy analyses in order to validate the role of wireless PNS as the standard of care.

Selective kappa-opioid antagonism ameliorates anhedonic behavior: evidence from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS).

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.

A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.

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.

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.

An Electrophysiological Biomarker That May Predict Treatment Response to ECT.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for major depression but also carries risk of cognitive side effects. The ability to predict whether treatment will be effective before initiation of treatment could significantly improve quality of care, reduce suffering, and diminish costs. We sought to carry out a comprehensive and definitive study of the relationship between the background electroencephalography (EEG) and therapeutic response to ECT. METHODS: Twenty-one channel resting EEG was collected pre-ECT and 2 to 3 days after ECT course from 2 separate data sets, one to develop an EEG model of therapeutic response (n = 30) and a second to test this model (n = 40). A 3-way principal components analysis was applied and coherence and spectral amplitude across 6 frequency bands were examined. The primary outcome measure was the Montgomery-Asberg Rating Scale (MADRS). RESULTS: Four patterns of amplitude and coherence along with baseline MADRS score accounted for 85% of the variance in posttreatment course MADRS score in study 1 (R = 0.85, F = 11.7, P < 0.0002) and 53% of the variance in MADRS score in study 2 (R = 0.53, F = 5.5, P < 0.003). Greater pre-ECT course anterior delta coherence accounted for the majority of variance in therapeutic response (study 1: R = 0.44, P = 0.01; study 2: R = 0.16, P = 0.008). CONCLUSIONS: These results suggest a putative electrophysiological biomarker that can predict therapeutic response before a course of ECT. Greater baseline anterior delta coherence is significantly associated with a better subsequent therapeutic response and could be indicative of intact circuitry allowing for improved seizure propagation.