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Background: Ketamine and esketamine are increasingly used for treatment-resistant depression (TRD), yet their hepatic safety profile with repeated or long-term use remains poorly characterized. Chronic recreational ketamine abuse has been linked to cholestasis and cholangiopathy, raising concern that therapeutic use may carry similar risks. No systematic data exist on liver enzyme trajectories or biliary injury at subanesthetic doses used for depression. Methods: This historical cohort study included adults with TRD receiving IV ketamine or intranasal (IN) esketamine at the Mayo Clinic Ketamine Clinic (2017 to 2024). Patients were eligible if they had at least one liver enzyme value (AST, ALT, ALP, or bilirubin) within 12 months before through 3 months after treatment. Longitudinal enzyme trajectories were modeled using generalized linear-mixed models with a Gamma distribution. Clinically significant elevation was defined as ≥2× the upper limit of normal (ULN). Wilcoxon signed-rank tests compared pretreatment and post-treatment paired values. Results: Of 104 enrolled patients, 74 had liver enzyme data available; 51 had post-initiation data. Median age was 51.5 years; 72% were female. Most (78.4%) received IV ketamine. No clinically meaningful changes in enzyme trajectories were observed. Three patients (5.9%) had elevations ≥2× ULN, all attributable to alcohol use, myalgias, or pre-existing hepatic steatosis rather than (es)ketamine. Conclusions: Subanesthetic IV ketamine (0.5 mg/kg) and FDA-approved IN esketamine doses were not associated with clinically significant liver enzyme elevations in this real-world TRD cohort. Current evidence does not support routine hepatic monitoring for asymptomatic patients, although prospective, larger-scale studies are needed to confirm these findings.

Objectives: The electroconvulsive therapy for the acute management of severe agitation in dementia (ECT-AD) trial is a multisite study evaluating the effectiveness of ECT for severe agitation in individuals with advanced dementia. Given that participants lack decisional capacity because of advanced cognitive impairment, the trial required a structured and ethically sound approach to obtaining informed consent and assent across jurisdictions with differing legal requirements, including Massachusetts, New York, Georgia, Minnesota, and Michigan. This paper describes the approach used in the study. Methods: We describe the consent framework developed for the ECT-AD trial, including procedures for identifying legally authorized representatives, complying with state-specific laws for ECT consent, obtaining surrogate consent for research participation, and assessing patient assent and dissent using a standardized tool. Conclusions: The approach used in this study may serve as a practical model for future research involving individuals without decision-making capacity and legally complex interventions such as ECT.

Background: Ketamine and esketamine ((es)ketamine) rapidly reduce depressive symptoms and suicidal ideation (SI) in treatment-resistant depression (TRD), but whether early SI improvement during the acute phase of the treatment predicts reduced suicide-associated emergency department (SAED) visits over the longer term remains unclear. Objectives: To examine whether early improvements in SI, measured using item 12 of the Quick Inventory of Depressive Symptomatology – Self Reported (QIDS-SR), following (es)ketamine treatment are associated with SAED visits over 6 months Design: Retrospective cohort study. Methods: Individuals with TRD who had available data on SI measured using the QIDS-SR during the acute phase, as well as data on SAED visits over 6 months, were included. Participants were classified based on changes in SI as resolved, partially improved, or unchanged/worsened using the QIDS-SR item 12 during acute treatment (up to six intravenous (IV) or eight intranasal (IN) treatments) and were followed for SAED visits. Results: Among 96 patients with SI data, 73 (76%) had baseline SI. Following acute-phase treatment, 36 (49%) achieved SI resolution, 14 (19%) partially improved, and 23 (32%) were unchanged/worsened. During the 6-month follow-up, 8 (11%) had post-acute SAED visits. While not statistically significant, patients with resolved SI had lower odds of post-acute ED visits (OR = 0.16, p = 0.12). Kaplan–Meier estimates of SAED visit-free survival across three SI change groups trended toward significance ( p = 0.066), suggesting lower cumulative healthcare (ED) utilization in more favorable change groups. Secondary analysis among 57 patients who received IV ketamine and had baseline SI showed that, after two infusions, 33 (47.2%) demonstrated a reduction in SI. Early SI improvement (⩾50% reduction in SI) was associated with a lower likelihood of any post-treatment SAED visit at 6 months after adjusting for pre-treatment SAED (OR = 0.17, 95% CI: 0.02–0.98, p = 0.047), corresponding to numbers needed to treat of 4.3. Conclusion: Early SI changes may have prognostic implications, though larger studies are needed to confirm clinical significance.

Background: Depression affects approximately 5.7% of adults worldwide, and around one-third of these individuals develop treatment-resistant depression (TRD). Intravenous (IV) ketamine and esketamine (administered IV or intranasally (IN)) are novel treatment options for TRD; however, only IN esketamine currently holds FDA approval. Objectives: Compare the acute effectiveness of IV ketamine with esketamine (IV or IN) in adults with TRD. Design: Mantel–Haenszel random-effects meta-analysis of head-to-head studies. Response and remission at study end point were co-primary outcomes, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses explored the impact of diagnosis, study type, and publication format; heterogeneity was quantified with I 2 . Data sources and methods: MEDLINE, Embase, Cochrane, APA Psycinfo, and Scopus were searched from inception through 19 March 2025. Eligible studies enrolled adults with unipolar or bipolar depression directly comparing IV ketamine with esketamine and reporting response or remission. Results: Screening 1089 records identified eight studies ( n = 978). Seven observational studies ( n = 915) comparing IV ketamine with IN esketamine were included in the meta-analysis, while one randomized controlled trial (RCT) comparing IV formulations was summarized qualitatively. Pooled response from six studies gave OR = 1.26 (95% CI, 0.92–1.71; p = 0.15) and remission from seven studies gave OR = 1.31 (95% CI, 0.93–1.86; p = 0.12), both nonsignificantly favoring IV ketamine with negligible heterogeneity ( I 2 = 0%). Sensitivity analyses excluding bipolar depression or abstract-only reports yielded similar effect estimates, reinforcing the robustness of the findings. Evidence across three studies for faster onset with IV ketamine ranged from significant in one study to modest trends in two. Conclusion: Based on the currently available comparative evidence, which is almost entirely observational, IV ketamine and IN esketamine show comparable acute response and remission rates, though IV ketamine may act faster. Large head-to-head RCTs are needed to confirm these findings. Trial registration: The study protocol was prospectively registered on the Open Science Framework (OSF) at https://osf.io/5jzev .

Background: Invasive and non-invasive neuromodulation in psychiatry represents a burgeoning field that leverages advanced neuromodulation techniques to address substance use disorders (SUDs). Aims: This narrative review synthesizes findings from multiple reviews to evaluate the efficacy of neuromodulation in treating SUDs. Methods: A comprehensive literature search was conducted between December 2024 and April 2025, focusing on systematic reviews and meta-analyses that examined various neuromodulation modalities, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). The selected reviews were analyzed to identify common themes, outcomes, and gaps in the current understanding of these treatments for SUDs. Results: 11 reviews met the final inclusion criteria; 5 focused on non-invasive neuromodulation (rTMS, tDCS) and 6 on invasive neuromodulation (DBS). Non-invasive neurostimulation was associated with modest improvements in craving and cognitive dysfunction in individuals with SUDs. Similarly, invasive neuromodulation (DBS), through high-frequency stimulation of the bilateral nucleus accumbens, appeared to reduce cravings and improve comorbid psychiatric symptoms in both preclinical and human studies. Importantly, small sample sizes, heterogeneity in targets and stimulation protocols, and short follow-up periods significantly limit the generalizability of current findings from both non-invasive and invasive neuromodulation studies. Conclusions: As novel and more effective therapies for the treatment of SUD are desperately needed, procedural interventional psychiatry holds promise. However, despite encouraging results, existing evidence is still preliminary, and larger, rigorously designed studies are warranted to further establish the safety and efficacy of neuromodulatory interventions for SUD treatment.

Importance The role and safety of transcranial electrical stimulation (tES) for treating depressive disorders remain under evaluation. Objective To evaluate tES treatment in patients with major depressive disorder (MDD) and comorbid depressive conditions. Data Sources A search of MEDLINE, Embase, Cochrane, APA PsycINFO, and Scopus databases was conducted from inception to September 17, 2024. Study Selection Randomized clinical trials (RCTs) of adults with MDD, depression with psychiatric comorbidities (DPC), or depression with medical comorbidities (DMC), treated with transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or transcranial random noise stimulation (tRNS), compared with sham or other treatments were included. Data Extraction and Synthesis Independent reviewers extracted data in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, with random-effects meta-analysis used for pooling. Main Outcomes and Measures Primary outcomes were depression severity, response and remission rates, and adverse events. Standardized mean differences (SMDs) were reported for continuous outcomes, and odds ratios (ORs) were reported for categorical outcomes. Quality of evidence (QOE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. Results The meta-analysis included 5522 participants from 114 study groups from 88 RCTs (3198 female [58.9%]; mean [range] age, 43.1 [19.4-76.9] years). Most studies (104 study groups from 79 RCTs [91.2%]) evaluated tDCS, while 7 study groups from 6 RCTs (6.1%) evaluated tACS, and 3 study groups from 3 RCTs (2.7%) evaluated tRNS. tES was associated with reduced depressive symptoms (SMD = −0.59; 95% CI, −0.83 to −0.35; low QOE) and improvement in DMC (SMD = −1.05; 95% CI, −1.67 to −0.43; low QOE) and DPC (SMD = −0.78; 95% CI, −1.27 to −0.29; low QOE) compared with MDD (SMD = −0.22; 95% CI, −0.44 to 0.01; low QOE). tDCS was associated with reduced depression in DMC (SMD = −1.05; 95% CI, −1.70 to −0.40; very low QOE) and DPC (SMD = −0.88; 95% CI, −1.40 to −0.36; low QOE) but not MDD. tACS was associated with improved MDD symptoms (SMD = −0.58; 95% CI, −0.96 to −0.20; high QOE) and response rates (OR, 2.07; 95% CI, 1.34 to 3.19; high QOE). Combined tDCS and medication was associated with reduced symptoms (SMD = −0.51; 95% CI, −0.90 to −0.13; moderate QOE) and increased response (OR, 2.25; 95% CI, 1.08 to 4.65; high QOE) in MDD. tDCS combined with psychotherapy was not associated with improvement. Subgroup analysis showed that anodal left dorsolateral prefrontal cortex DCS was associated with improved outcomes. Mild to moderate adverse events were more frequent in tES groups. Conclusions and Relevance In this systematic review and meta-analysis, tDCS was associated with improvement in depression among patients with DMC and DPC (with smaller benefits in MDD), tACS was associated with improved MDD outcomes (while tRNS had insufficient evidence) in smaller samples, and combined tDCS and medication was associated with improvement in depression. These findings suggest that tES is well-tolerated overall, with only mild to moderate adverse events, and that future research should optimize stimulation parameters and individualize tES interventions.

Abstract Electroconvulsive therapy (ECT) is an effective treatment for severe depression, especially in treatment-resistant cases. However, its potential cognitive side effects necessitate careful dosing to balance therapeutic benefits and cognitive stability. Recent advances in electric field (E-field) modeling offer promising avenues to optimize ECT dosing. This review synthesizes current knowledge on E-field modeling in ECT and explores its clinical applications. It examines the variability in E-field strengths and distributions induced by ECT and their impact on clinical outcomes. Additionally, the relationship between E-field strengths, neuroplasticity, and therapeutic efficacy is discussed. Translational studies of E-field-informed ECT are highlighted, emphasizing individualized optimal amplitude dosing and potential clinical applications. This review provides useful insights into how E-field modeling can improve the effectiveness of ECT while minimizing adverse effects, helping guide future research and clinical practice.

Objective To describe the immediate clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) in treating long COVID symptoms. Long COVID currently impacts approximately 5.3% of US adults, presenting with persistent fatigue, depression, anxiety, cognitive impairments, and social function decline. Repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex has improved these symptoms in some studies. Methods Five patients (ages 52–63 years, 3 female patients) underwent accelerated rTMS using intermittent theta burst stimulation (600 pulses over 3 minutes 20 seconds, 80%–120% of resting motor threshold) to the left dorsolateral prefrontal cortex. The treatment consisted of twice-daily sessions over 20–30 treatments. Outcomes were measured using the Patient-Reported Outcomes Measurement and Information System (PROMIS) questionnaires, assessing fatigue, depression, anxiety, cognitive function, and social function at baseline and immediately posttreatment. Results One patient discontinued immediately due to intolerable scalp pain. Posttreatment PROMIS scores showed the following: fatigue decreased from 74.5 to 61.8, depression from 60.3 to 51.5, and anxiety from 62.0 to 54.0. Scores increased for cognitive (26.8 to 32.3) and social (31.0 to 32.5) function. These changes, although not statistically significant, indicate a trend toward symptom reduction. Subjectively, 3 of 4 patients who completed the rTMS course reported improvements. Conclusion This case series suggests that rTMS may offer symptomatic relief in long COVID patients. Although the observed improvements in PROMIS were not statistically significant, even minimal improvements are clinically significant for patients enduring prolonged suffering. These preliminary findings are encouraging and underscore the need for further research with larger cohorts to validate the efficacy of rTMS in long COVID symptom relief.

Objectives Electroconvulsive therapy (ECT) is considered to be the most effective treatment for severe depression. This study investigated recent ECT outcomes for depression at a large tertiary center, which also provides community care. Methods Data were obtained from Mayo Clinic Rochester patients ages 18 and older who received an acute course of ECT between August 1, 2017 and April 30, 2024. Patients were included if there was a depressive disorder diagnosis (unipolar or bipolar) and a self-rated Patient Health Questionnaire-9 (PHQ-9) within 10 days of the start and end of the acute course. Patients were excluded if the starting PHQ-9 score was less than 10. The age, sex, number of acute course treatments, stimulus electrode lead placement, and PHQ-9 scores were collected. Response (PHQ-9 improvement ≥50%) and remission (PHQ-9 < 5) rates were calculated. Linear and logistic regressions were performed to investigate predictors of response and remission. Results Of 1206 patients identified, 408 met final inclusion and exclusion criteria. The response rate was 80.4%, and remission rate was 52.7%. Logistic regression for response showed no significant predictors; the P value for age just missed statistical significance (odds ratio, 1.0152; 95% confidence interval, 0.9991–1.0316; P = 0.0641). Logistic regression for remission showed only a lower baseline PHQ-9 score (odds ratio, 0.9465; 95% confidence interval, 0.9049–0.9891; P = 0.0152) as a significant predictor. Conclusions Our results affirmed the high efficacy of ECT in severe depression. No other established treatment for depression can report a response rate as high as 80% in a naturalistic study. This study supports the continued relevance and place of ECT for severe depression.

Abstract Introduction Although there are studies assessing reasons for antidepressant discontinuation, little is known about the impact of sex differences or cytochrome P450 phenotypes. Our objective is to assess discontinuation rates between males and females and whether CYP450 phenotype influences discontinuation. Methods This is a retrospective review of patients previously enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment database with major depressive disorder. Patients were evaluated for antidepressants trialed between January 1, 2009, and September 30, 2019. Survival analyses with competing risks were used to analyze discontinuation reasons. A Kaplan-Meier estimation method was used to assess the time to discontinuation and discontinuation rates. Analyses were also completed to assess discontinuation between men and women by phenotypic groups. All tests were two-sided, and p-values ≤ .05 were considered statistically significant. Results There were 620 antidepressant discontinuation events discovered from 1015 antidepressant trials included. Overall, the median time to discontinuation for males was 2.6 years and 1.9 years for females (hazard ratio [HR] 0.97 [95% confidence interval (CI): 0.80, 1.19], p = .77). The risk of discontinuation was not different between males and females in any of the phenotype groups, which was consistent in the multivariable analyses. Concomitant use of medications that inhibited or induced antidepressant metabolism increased the overall risk of discontinuation (HR 1.45, 95% CI [1.06, 1.99], p = .020) in a time-dependent analysis. Discussion We did not detect a significant difference in risk of antidepressant discontinuation rates between males and females even when accounting for cytochrome P450 phenotype. Future studies should account for whether medications that inhibit or induce antidepressant metabolism may be a crucial factor in antidepressant discontinuation.