Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in patients with depression, yet treatment response remains variable. While previous work has identified predictors of remission in younger adults, relatively little data exists in late-life depression (LLD). To address this gap, data from 164 participants with LLD from a randomized non-inferiority treatment trial comparing standard bilateral rTMS to bilateral theta burst stimulation (TBS) (ClinicalTrials.gov identifier: NCT02998580) were analyzed using binary logistic regression and conditional inference tree (CIT) modeling. Lower baseline depression symptom severity, fewer prior antidepressant treatment failures, and higher global cognition predicted remission following rTMS treatment. The CIT predicted a higher likelihood of achieving remission for patients with a total score of 19 or lower on the Montgomery-Åsberg Depression Rating Scale, 1 or fewer prior antidepressant treatment failures, and a total score of 23 or higher on the Montreal Cognitive Assessment. Our results indicate that older adults with lower severity of depression, fewer antidepressant treatment failures, and higher global cognition benefit more from current forms of rTMS. The results suggest that there is potentially higher value in using rTMS earlier in the treatment pathway for depression in older adults.

Amplitude-determined seizure-threshold, electric field modeling, and electroconvulsive therapy antidepressant and cognitive outcomes.

Electroconvulsive therapy (ECT) pulse amplitude, which dictates the induced electric field (E-field) magnitude in the brain, is presently fixed at 800 or 900 milliamperes (mA) without clinical or scientific rationale. We have previously demonstrated that increased E-field strength improves ECT's antidepressant effect but worsens cognitive outcomes. Amplitude-determined seizure titration may reduce the E-field variability relative to fixed amplitude ECT. In this investigation, we assessed the relationships among amplitude-determined seizure-threshold (STa), E-field magnitude, and clinical outcomes in older adults (age range 50 to 80 years) with depression. Subjects received brain imaging, depression assessment, and neuropsychological assessment pre-, mid-, and post-ECT. STa was determined during the first treatment with a Soterix Medical 4×1 High Definition ECT Multi-channel Stimulation Interface (Investigation Device Exemption: G200123). Subsequent treatments were completed with right unilateral electrode placement (RUL) and 800 mA. We calculated Ebrain defined as the 90th percentile of E-field magnitude in the whole brain for RUL electrode placement. Twenty-nine subjects were included in the final analyses. Ebrain per unit electrode current, Ebrain/I, was associated with STa. STa was associated with antidepressant outcomes at the mid-ECT assessment and bitemporal electrode placement switch. Ebrain/I was associated with changes in category fluency with a large effect size. The relationship between STa and Ebrain/I extends work from preclinical models and provides a validation step for ECT E-field modeling. ECT with individualized amplitude based on E-field modeling or STa has the potential to enhance neuroscience-based ECT parameter selection and improve clinical outcomes.

A Novel Approach to Monitoring Cognitive Adverse Events for Interventional Studies Involving Advanced Dementia Patients: Insights From the Electroconvulsive Therapy for Agitation in Dementia Study.

OBJECTIVE: To develop an individualized method for detecting cognitive adverse events (CAEs) in the context of an ongoing trial of electroconvulsive therapy for refractory agitation and aggression for advanced dementia (ECT-AD study). METHODS: Literature search aimed at identifying (a) cognitive measures appropriate for patients with advanced dementia, (b) functional scales to use as a proxy for cognitive status in patients with floor effects on baseline cognitive testing, and (c) statistical approaches for defining a CAE, to develop CAEs monitoring plan specifically for the ECT-AD study. RESULTS: Using the Severe Impairment Battery-8 (SIB-8), baseline floor effects are defined as a score of ≤5/16. For patients without floor effects, a decline of ≥6 points is considered a CAE. For patients with floor effects, a decline of ≥30 points from baseline on the Barthel Index is considered a CAE. These values were derived using the standard deviation index (SDI) approach to measuring reliable change. CONCLUSIONS: The proposed plan accounts for practical and statistical challenges in detecting CAEs in patients with advanced dementia. While this protocol was developed in the context of the ECT-AD study, the general approach can potentially be applied to other interventional neuropsychiatric studies that carry the risk of CAEs in patients with advanced dementia.

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.

Hippocampal subfield volumes in treatment resistant depression and serial ketamine treatment.

Introduction: Subanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance. Methods: Patients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction. Results: Patients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007). Discussion: These results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.

Effect of prior pharmacotherapy on remission with sequential bilateral theta-burst versus standard bilateral repetitive transcranial magnetic stimulation in treatment-resistant late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is used for treatment of late-life depression. In the FOUR-D study, sequential bilateral theta-burst stimulation (TBS) had comparable remission rates to standard bilateral rTMS. Data were analysed from the FOUR-D trial to compare remission rates between two types of rTMS based on the number and class of prior medication trials. The remission rate was higher in participants with ≤1 previous trial (43.9%) than in participants with 2 previous trials (26.5%) or ≥3 previous trials (24.6%; χ² = 6.36, d.f. = 2, P = 0.04). Utilising rTMS earlier in late-life depression may lead to better outcomes.

Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression.

INTRODUCTION: Ketamine treatment prompts a rapid antidepressant response in treatment-resistant depression (TRD). We performed an exploratory investigation of how ketamine treatment in TRD affects different cognitive domains and relates to antidepressant response. METHODS: Patients with TRD (N = 66; 30 M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg). Neurocognitive function and depressive symptoms were assessed at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks following end of treatment. Mixed effect models tested for changes in seven neurocognitive domains and antidepressant response, with post-hoc pairwise comparisons between timepoints, including follow-up. Relationships between change in neurocognitive function and antidepressant response over the course of treatment were tested with Pearson's correlation and mediation analyses. Associations between baseline neurocognitive performance and antidepressant response were tested with Pearson's correlation. RESULTS: Significant improvements in inhibition, working memory, processing speed, and overall fluid cognition were observed after the first and fourth ketamine infusion. Improvements in processing speed and overall fluid cognition persisted through follow-up. Significant improvements in depressive symptoms reverted towards baseline at follow-up. Baseline working memory and change in inhibition were moderately correlated with antidepressant response, however, improvements in neurocognitive performance were statistically independent from antidepressant response. CONCLUSION: Antidepressant ketamine leads to improved neurocognitive function, which persist for at least 5 weeks. Neurocognitive improvements observed appear independent of antidepressant response, suggesting ketamine may target overlapping but distinct functional brain systems. Limitations Research investigating repeated serial ketamine treatments is important to determine cognitive safety. This study is a naturalistic design and does not include placebo.

Electric Field, Ictal Theta Power, and Clinical Outcomes in Electroconvulsive Therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is efficacious for treatment-resistant depression. Treatment-induced cognitive impairment can adversely impact functional outcomes. Our pilot study linked the electric field to ictal theta power from a single suprathreshold treatment and linked ictal theta power to changes in phonemic fluency. In this study, we set out to replicate our findings and expand upon the utility of ictal theta power as a potential cognitive biomarker. METHODS: Twenty-seven participants (18 female and 9 male) received right unilateral ECT for treatment-resistant depression. Pre-ECT magnetic resonance imaging and finite element modeling determined the 90th percentile maximum electric field in the brain. Two-lead electroencephalographs were digitally captured across the ECT course, with the earliest suprathreshold treatment used to determine power spectral density. Clinical and cognitive outcomes were assessed pre-, mid-, and post-ECT. We assessed the relationship between the electric field in the brain, ictal theta power, clinical outcome (Inventory of Depressive Symptomatology), and cognitive outcomes (phonemic and semantic fluency) with linear models. RESULTS: Ictal theta power in the Fp1 and Fp2 channels was associated with the electric field, antidepressant outcome, and phonemic and semantic fluency. The relationship between ictal theta power and phonemic fluency was strengthened in the longitudinal analysis. The electric field in the brain was directly associated with phonemic and semantic fluency but not with antidepressant outcome. CONCLUSIONS: Ictal theta power is a potential cognitive biomarker early on in the ECT course to help guide parameter changes. Larger studies are needed to further assess ictal theta power's role in predicting mood outcome and changes with ECT parameters.

Cerebro-cerebellar functional neuroplasticity mediates the effect of electric field on electroconvulsive therapy outcomes.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression and works by applying an electric current through the brain. The applied current generates an electric field (E-field) and seizure activity, changing the brain's functional organization. The E-field, which is determined by electrode placement (right unilateral or bitemporal) and pulse amplitude (600, 700, or 800 milliamperes), is associated with the ECT response. However, the neural mechanisms underlying the relationship between E-field, functional brain changes, and clinical outcomes of ECT are not well understood. Here, we investigated the relationships between whole-brain E-field (Ebrain, the 90th percentile of E-field magnitude in the brain), cerebro-cerebellar functional network connectivity (FNC), and clinical outcomes (cognitive performance and depression severity). A fully automated independent component analysis framework determined the FNC between the cerebro-cerebellar networks. We found a linear relationship between Ebrain and cognitive outcomes. The mediation analysis showed that the cerebellum to middle occipital gyrus (MOG)/posterior cingulate cortex (PCC) FNC mediated the effects of Ebrain on cognitive performance. In addition, there is a mediation effect through the cerebellum to parietal lobule FNC between Ebrain and antidepressant outcomes. The pair-wise t-tests further demonstrated that a larger Ebrain was associated with increased FNC between cerebellum and MOG and decreased FNC between cerebellum and PCC, which were linked with decreased cognitive performance. This study implies that an optimal E-field balancing the antidepressant and cognitive outcomes should be considered in relation to cerebro-cerebellar functional neuroplasticity.

Assessing Depressive Symptoms in Patients With Cancer Treated With Interleukin-2: A Comparison of 2 Measures.

BACKGROUND: High-dose interleukin-2 is a therapy available for individuals with renal cell carcinoma; however, it can produce adverse effects, specifically depressive symptoms. There is limited information regarding the trajectory of depressive symptoms and measurement-based care assessment of depressive symptoms. OBJECTIVE: The purpose was to describe the trajectory of depressive symptoms and compare 2 depression measures. METHODS: A descriptive, mixed-method case study approach was used to describe the longitudinal trajectory of depressive symptoms The qualitative assessment included a journal entry and an interview. The quantitative depression symptom severity measures included the 8-item self-report Patient-Reported Outcomes Measurement Information System Depression and the 30-item Inventory of Depressive Symptomatology-Clinician Rated (IDS-C). RESULTS: Ten cases were enrolled. The maximum number of interleukin-2 doses that any patient received within a single hospitalization ranged from 4 to 12. Mean scores on the 8-item Patient-Reported Outcomes Measurement Information System Depression showed no changes in depressive symptoms from pretreatment to posttreatment, nor across hospitalizations. Mean total scores on the IDS-C increased from "normal" to "mild severity" depressive symptom range across all treatment cycles, suggesting transient depressive symptoms within hospitalizations. Qualitative data from the case supported the IDS-C increase, suggesting that the patient developed depressive symptoms pretreatment to posttreatment. CONCLUSIONS: Understanding the trajectory of depressive symptoms allows for the identification of critical time points when depressive symptoms present and change across treatment. It is critical to use measurement-based care using validated measures to assess for the presence and changes in depressive symptoms. IMPLICATIONS FOR PRACTICE: Validated self-report or clinician-rated depression symptom measures should be used to document the presence or absence of depressive symptoms in this population.

Links between electroconvulsive therapy responsive and cognitive impairment multimodal brain networks in late-life major depressive disorder.

BACKGROUND: Although electroconvulsive therapy (ECT) is an effective treatment for depression, ECT cognitive impairment remains a major concern. The neurobiological underpinnings and mechanisms underlying ECT antidepressant and cognitive impairment effects remain unknown. This investigation aims to identify ECT antidepressant-response and cognitive-impairment multimodal brain networks and assesses whether they are associated with the ECT-induced electric field (E-field) with an optimal pulse amplitude estimation. METHODS: A single site clinical trial focused on amplitude (600, 700, and 800 mA) included longitudinal multimodal imaging and clinical and cognitive assessments completed before and immediately after the ECT series (n = 54) for late-life depression. Another two independent validation cohorts (n = 84, n = 260) were included. Symptom and cognition were used as references to supervise fMRI and sMRI fusion to identify ECT antidepressant-response and cognitive-impairment multimodal brain networks. Correlations between ECT-induced E-field within these two networks and clinical and cognitive outcomes were calculated. An optimal pulse amplitude was estimated based on E-field within antidepressant-response and cognitive-impairment networks. RESULTS: Decreased function in the superior orbitofrontal cortex and caudate accompanied with increased volume in medial temporal cortex showed covarying functional and structural alterations in both antidepressant-response and cognitive-impairment networks. Volume increases in the hippocampal complex and thalamus were antidepressant-response specific, and functional decreases in the amygdala and hippocampal complex were cognitive-impairment specific, which were validated in two independent datasets. The E-field within these two networks showed an inverse relationship with HDRS reduction and cognitive impairment. The optimal E-filed range as [92.7-113.9] V/m was estimated to maximize antidepressant outcomes without compromising cognitive safety. CONCLUSIONS: The large degree of overlap between antidepressant-response and cognitive-impairment networks challenges parameter development focused on precise E-field dosing with new electrode placements. The determination of the optimal individualized ECT amplitude within the antidepressant and cognitive networks may improve the treatment benefit-risk ratio. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02999269.

Effectiveness of Standard Sequential Bilateral Repetitive Transcranial Magnetic Stimulation vs Bilateral Theta Burst Stimulation in Older Adults With Depression: The FOUR-D Randomized Noninferiority Clinical Trial.

Importance: Treatment-resistant depression (TRD) is common in older adults. Bilateral repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex for 48 minutes has demonstrated efficacy in TRD. Theta burst stimulation (TBS), a newer form of rTMS, can also be delivered bilaterally using left intermittent TBS and right continuous TBS for only 4 minutes. Objective: To establish the effectiveness and tolerability of TBS compared with standard rTMS in older adults with TRD. Design, Setting, and Participants: In this randomized noninferiority trial with open treatment and blinded assessors, recruitment occurred between December 2016 and March 2020. The trial was conducted at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada and included outpatients 60 years and older with a diagnosis of depression, moderate severity, and nonresponse to 1 or more antidepressant trial of adequate dosage and duration or intolerance of 2 or more trials. Interventions: Participants were randomized to receive a course of 4 to 6 weeks of either bilateral standard rTMS or TBS. Main Outcomes and Measures: The primary outcome measure was change in Montgomery-Åsberg Depression Rating Scale; secondary outcome measures included the 17-item Hamilton Rating Scale for Depression, Quick Inventory of Depressive Symptomatology (16-item) (self-report), and dropout rates. A noninferiority margin of 2.75 points was used for the primary outcome. All participants who attained the primary completion point of 4 weeks were analyzed. Results: A total of 87 participants (mean [SD] age, 67.1 [6.7] years; 47 [54.0%] female) were randomized to standard bilateral rTMS and 85 (mean [SD] age, 66.3 [5.3] years; 45 [52.9%] female) to TBS, of whom 85 (98%) and 79 (93%) were assessed for the primary outcome, respectively, whereas tolerability was assessed in all randomized participants. In the rTMS group, 4 (4.6%) were American Indian, reported other, or preferred not to answer; 5 (5.8%) were Asian; and 78 (89.7%) were White. In the TBS group, 6 (7.1%) were Asian, 2 (2.4%) were Black or reported other, and 77 (90.3%) were White. Mean (SD) Montgomery-Åsberg Depression Rating Scale total scores improved from 25.6 (4.0) to 17.3 (8.9) for rTMS and 25.7 (4.7) to 15.8 (9.1) for TBS (adjusted difference, 1.55; lower 95% CI -0.67), establishing noninferiority for TBS. The all-cause dropout rates were relatively similar between groups (rTMS: 2 of 87 [2.3%]; TBS: 6 of 85 [7.1%]; P = .14; χ2 = 2.2). Conclusions and Relevance: In older adults with TRD, bilateral TBS compared with standard bilateral rTMS achieved noninferior reduction in depression symptoms. Both treatments had low and similar dropout rates. Using TBS rather than rTMS could increase access to treatment several-fold for older adults with TRD. Trial Registration: ClinicalTrials.gov Identifier: NCT02998580.

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.

Ictal Theta Power as an Electroconvulsive Therapy Safety Biomarker: A Pilot Study.

OBJECTIVE: Electroconvulsive therapy (ECT) remains the benchmark for treatment resistant depression, yet its cognitive adverse effects have a negative impact on treatment. A predictive safety biomarker early in ECT treatment is needed to identify patients at cognitive risk to maximize therapeutic outcomes and minimize adverse effects. We used ictal electroencephalography frequency analysis from suprathreshold treatments to assess the relationships between ECT dose, ictal power across different frequency domains, and cognitive outcomes. METHODS: Seventeen subjects with treatment resistant depression received right unilateral ECT. Structural magnetic resonance imaging was obtained pre-ECT for electric field modeling to assess ECT dose. Serial assessments with 24-lead electroencephalography captured ictal activity. Clinical and cognitive assessments were performed before and after ECT. The primary cognitive outcome was the change in Delis Kaplan Executive Function Verbal Fluency Letter Fluency. RESULTS: Ictal theta (4-8 Hz) power in the Fp1/Fp2 channels was associated with both whole-brain electric field strength (t(2,12) = 19.5, P = 0.007)/(t(2,10) = 21.85, P = 0.02) and Delis Kaplan Executive Function Verbal Fluency Letter Fluency scores (t(2,12) = -2.05, P = 0.05)/(t(2,10) = -2.20, P = 0.01). Other frequency bands (beta, alpha, delta, and gamma) did not demonstrate this relationship. CONCLUSIONS: This pilot data identify ictal theta power as a potential safety biomarker in ECT and is related to the strength of the ECT dose. Ictal theta power could prove to be a convenient and powerful tool for clinicians to identify those patients most susceptible to cognitive impairment early in the treatment series. Additional studies are needed to assess the role of longitudinal changes in ictal theta power throughout the ECT series.

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.

Electroconvulsive therapy, electric field, neuroplasticity, and clinical outcomes.

Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes, but the underlying mechanisms for antidepressant response and procedure-induced cognitive side effects have yet to be elucidated. Such mechanisms may be complex and involve certain ECT parameters and brain regions. Regarding parameters, the electrode placement (right unilateral or bitemporal) determines the geometric shape of the electric field (E-field), and amplitude determines the E-field magnitude in select brain regions (e.g., hippocampus). Here, we aim to determine the relationships between hippocampal E-field strength, hippocampal neuroplasticity, and antidepressant and cognitive outcomes. We used hippocampal E-fields and volumes generated from a randomized clinical trial that compared right unilateral electrode placement with different pulse amplitudes (600, 700, and 800 mA). Hippocampal E-field strength was variable but increased with each amplitude arm. We demonstrated a linear relationship between right hippocampal E-field and right hippocampal neuroplasticity. Right hippocampal neuroplasticity mediated right hippocampal E-field and antidepressant outcomes. In contrast, right hippocampal E-field was directly related to cognitive outcomes as measured by phonemic fluency. We used receiver operating characteristic curves to determine that the maximal right hippocampal E-field associated with cognitive safety was 112.5 V/m. Right hippocampal E-field strength was related to the whole-brain ratio of E-field strength per unit of stimulation current, but this whole-brain ratio was unrelated to antidepressant or cognitive outcomes. We discuss the implications of optimal hippocampal E-field dosing to maximize antidepressant outcomes and cognitive safety with individualized amplitudes.