Effects of ketamine on metabolic parameters in depressive disorders: A systematic review.

BACKGROUND: Persons with Major Depressive Disorder (MDD), notably treatment-resistant depression (TRD), are differentially affected by type 2 diabetes mellitus and associated morbidity. Ketamine is highly efficacious in the treatment of adults living with MDD, notably TRD. Herein, we sought to determine the effect of ketamine on metabolic parameters in animal stress paradigms and human studies. METHODS: We performed a comprehensive search on PubMed, OVID, and Scopus databases for primary research articles from inception to May 5, 2024. Study screening and data extraction were performed by two reviewers (S.W. and G.H.L.). Both preclinical and clinical studies were included in this review. RESULTS: Results from the preclinical studies indicate that in experimental diabetic conditions, ketamine does not disrupt glucose-insulin homeostasis. Within adults with MDD, ketamine is associated with GLUT3 transporter upregulation and differentially affects metabolomic signatures. In adults with TRD, ketamine induces increased brain glucose uptake in the prefrontal cortex. Available evidence suggests that ketamine does not adversely affect metabolic parameters. LIMITATIONS: There are a paucity of clinical studies evaluating the effects of ketamine on glucose-insulin homeostasis in adults with MDD. CONCLUSIONS: Our results indicate that ketamine is not associated with significant and/or persistent disruptions in metabolic parameters. Available evidence indicates that ketamine does not adversely affect glucose-insulin homeostasis. These results underscore ketamine's efficacy and safety as an antidepressant treatment that is not associated with metabolic disturbances commonly reported with current augmentation therapies.

Exploring vortioxetine combination with intranasal esketamine: A feasible alternative to SSRI/SNRI? - Insights from the REAL-ESK study.

BACKGROUND: Treatment-Resistant Depression (TRD) affects almost 30 % of patients with Major Depressive Disorder (MDD). Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD in combination with a Serotonin Specific Reuptake Inhibitor/SSRI or a Serotonin-Norepinephrine Reuptake Inhibitor/SNRI. There is a lack of studies investigating the effectiveness and safety of ESK-NS in combination with other oral antidepressants. AIM: To assess the efficacy of Vortioxetine plus ESK-NS in mitigating depressive symptoms and emotional blunting, as well as its tolerability in TRD subjects, compared to the standard-of-care of SSRI/SNRI plus ESK-NS. METHODS: We conducted a post-hoc analysis of the REAL-ESK study. The study included twenty TRD patients, ten subjects taking Vortioxetine as the main oral antidepressant with ESK-NS, and ten subjects taking SSRI or SNRI with ESK-NS. Psychometric assessments (Montgomery-Åsberg Depression Rating Scale/MADRS, Brief Psychiatric Rating Scale/BPRS) were conducted at baseline(T0), one month(T1), and three months after the treatment initiation(T2). RESULTS: The combination of Vortioxetine and ESK-NS was as effective as the standard-of-care in reducing depressive symptoms, with a higher effect size in reducing emotional blunting at T2. The safety and tolerability profile of the Vortioxetine+ESK-NS combination appeared to be better, with a lower rate of treatment-emergent adverse events. CONCLUSION: The combination of Vortioxetine and ESK-NS may be a valuable alternative to the standard-of-care SSRI/SNRI plus ESK-NS in TRD patients, particularly regarding the reduction of emotional blunting and potentially a better safety and tolerability profile. Further randomized controlled trials with larger sample sizes and prospective designs are needed to confirm these findings.

Adaptive Immune Receptor Distinctions Along the Colorectal Polyp-Tumor Timelapse.

INTRODUCTION: Colorectal cancer (CRC) is the third-most common cancer diagnosed worldwide, with 1.85 million new cases per year. While mortality has significantly decreased due to preventive colonoscopy, only 5% of polyps identified progress to cancer. Studies have found that immunological alterations in other solid tumor microenvironments are associated with worse prognoses. METHODS: We applied an immunogenomics approach to assess adaptive immune receptor gene expression changes that were associated with development of adenocarcinoma, utilizing 79 samples that represented normal, tubular, villous, and tumor colorectal tissue for 32 patients. RESULTS: Results indicated that the number of productive TRD and TRG recombination reads, representing gamma-delta (γδ) T-cells, significantly decreased with progression from normal to tumor tissue. A further assessment of two independent CRC datasets was consistent with a decrease in TRD recombination reads with progression to CRC. Further, we identified three physicochemical parameters for immunoglobulin, complementarity determining region-3 (CDR3) amino acids associated with progression from normal to tumor tissue. CONCLUSIONS: Overall, this study points towards a need for further investigation of γδ T-cells in relation to CRC development; and indicates immunoglobulin CDR3 physicochemical features as potential CRC biomarkers.

Overcoming treatment-resistant depression with machine-learning based tools: a study protocol combining EEG and clinical data to personalize glutamatergic and brain stimulation interventions (SelecTool Project).

Treatment-Resistant Depression (TRD) poses a substantial health and economic challenge, persisting as a major concern despite decades of extensive research into novel treatment modalities. The considerable heterogeneity in TRD's clinical manifestations and neurobiological bases has complicated efforts toward effective interventions. Recognizing the need for precise biomarkers to guide treatment choices in TRD, herein we introduce the SelecTool Project. This initiative focuses on developing (WorkPlane 1/WP1) and conducting preliminary validation (WorkPlane 2/WP2) of a computational tool (SelecTool) that integrates clinical data, neurophysiological (EEG) and peripheral (blood sample) biomarkers through a machine-learning framework designed to optimize TRD treatment protocols. The SelecTool project aims to enhance clinical decision-making by enabling the selection of personalized interventions. It leverages multi-modal data analysis to navigate treatment choices towards two validated therapeutic options for TRD: esketamine nasal spray (ESK-NS) and accelerated repetitive Transcranial Magnetic Stimulation (arTMS). In WP1, 100 subjects with TRD will be randomized to receive either ESK-NS or arTMS, with comprehensive evaluations encompassing neurophysiological (EEG), clinical (psychometric scales), and peripheral (blood samples) assessments both at baseline (T0) and one month post-treatment initiation (T1). WP2 will utilize the data collected in WP1 to train the SelecTool algorithm, followed by its application in a second, out-of-sample cohort of 20 TRD subjects, assigning treatments based on the tool's recommendations. Ultimately, this research seeks to revolutionize the treatment of TRD by employing advanced machine learning strategies and thorough data analysis, aimed at unraveling the complex neurobiological landscape of depression. This effort is expected to provide pivotal insights that will promote the development of more effective and individually tailored treatment strategies, thus addressing a significant void in current TRD management and potentially reducing its profound societal and economic burdens.

Combination of Transcranial Magnetic Stimulation and Ketamine in Treatment-Resistant Depression: A Systematic Review.

Treatment-resistant depression (TRD) is a significant challenge in psychiatric practice, affecting a substantial proportion of patients with major depressive disorder (MDD). Traditional treatment modalities often fall short, necessitating the exploration of alternative therapies. This literature review examines the combined use of Transcranial Magnetic Stimulation (TMS) and ketamine in treating TRD. The objective of this study is to evaluate the efficacy, safety, and potential synergies of combining TMS and ketamine in the treatment of TRD. A comprehensive literature search was conducted using PubMed and Google Scholar databases from 2014 to 2024. The search terms included combinations of "Transcranial Magnetic Stimulation," "Ketamine," "Depression," "Major Depressive Disorder," "Treatment-Resistant Depression," and "Combination." After screening for relevance and applying inclusion and exclusion criteria, six studies were selected for review, including three case reports, a retrospective study, a pilot study, and a review study. The selected studies demonstrated that the combination of TMS and ketamine resulted in substantial and sustained improvement in depressive symptoms for patients with TRD. Case reports and retrospective studies highlighted significant reductions in depression severity and improvements in psychosocial functioning. The combination therapy showed a higher efficacy compared to monotherapies of either TMS or ketamine alone. Notably, adverse effects were generally mild and transient, with no severe adverse events reported in most studies. In conclusion, the combination of TMS and ketamine presents a promising treatment modality for patients with TRD, offering significant improvements in depressive symptoms and better outcomes compared to traditional monotherapies. However, the heterogeneity in study designs and small sample sizes underline the need for larger, randomized controlled trials to establish standardized protocols and further validate these findings.

Genetic factors and symptom dimensions associated with antidepressant treatment outcomes: clues for new potential therapeutic targets?

Treatment response and resistance in major depressive disorder (MDD) show a significant genetic component, but previous studies had limited power also due to MDD heterogeneity. This literature review focuses on the genetic factors associated with treatment outcomes in MDD, exploring their overlap with those associated with clinically relevant symptom dimensions. We searched PubMed for: (1) genome-wide association studies (GWASs) or whole exome sequencing studies (WESs) that investigated efficacy outcomes in MDD; (2) studies examining the association between MDD treatment outcomes and specific depressive symptom dimensions; and (3) GWASs of the identified symptom dimensions. We identified 13 GWASs and one WES of treatment outcomes in MDD, reporting several significant loci, genes, and gene sets involved in gene expression, immune system regulation, synaptic transmission and plasticity, neurogenesis and differentiation. Nine symptom dimensions were associated with poor treatment outcomes and studied by previous GWASs (anxiety, neuroticism, anhedonia, cognitive functioning, melancholia, suicide attempt, psychosis, sleep, sociability). Four genes were associated with both treatment outcomes and these symptom dimensions: CGREF1 (anxiety); MCHR1 (neuroticism); FTO and NRXN3 (sleep). Other overlapping signals were found when considering genes suggestively associated with treatment outcomes. Genetic studies of treatment outcomes showed convergence at the level of biological processes, despite no replication at gene or variant level. The genetic signals overlapping with symptom dimensions of interest may point to shared biological mechanisms and potential targets for new treatments tailored to the individual patient's clinical profile.

Comparison between Single-Dose and Two-Dose Psilocybin Administration in the Treatment of Major Depression: A Systematic Review and Meta-Analysis of Current Clinical Trials.

Current pharmacological treatments for major depressive disorder (MDD) are often only partially effective, with many patients experiencing no significant benefit, leading to treatment-resistant depression (TRD). Psilocybin, a classical serotonergic psychedelic, has emerged as a notable emerging treatment for such disorders. The aim of this systematic review and meta-analysis is to summarize and discuss the most recent evidence about the therapeutic effects of single-dose and two-dose psilocybin administration on the severity of depressive symptoms, as well as compare the efficacy of these interventions among patients with a primary diagnosis of MDD or TRD. Articles were collected from EBSCOhost and PubMed following the PRISMA guidelines, yielding 425 articles with 138 duplicates. After screening 287 records, 12 studies met the eligibility criteria and were included in the review. A quantitative analysis of the studies indicates that psilocybin is highly effective in reducing depressive symptoms severity among patients with primary MDD or TRD. Both single-dose and two-dose psilocybin treatments significantly reduced depressive symptoms severity, with two-dose administration sometimes yielding more pronounced and lasting effects. However, it is unclear if this was solely due to dosage or other factors. Future research should include standardized trials comparing these dosing strategies to better inform clinical practice.

Unraveling epigenomic signatures and effectiveness of electroconvulsive therapy in treatment-resistant depression patients: a prospective longitudinal study.

BACKGROUND: Electroconvulsive therapy (ECT) benefits patients with treatment-resistant depression (TRD), but the underlying biological processes are unclear. We conducted an epigenome-wide association study in 32 TRD patients undergoing ECT to depict ECT-associated methylation changes. Illness severity and ECT outcomes were assessed with the Montgomery-Åsberg Depression Rating Scale at baseline (T0) and 1 month after its end (T1). Methylation was profiled at T0 and T1 with the Illumina Infinium Methylation EPIC BeadChip array. RESULTS: Longitudinal T0-T1 analyses showed 3 differentially methylated probes (DMPs) with nominal p values ≤ 10-5, with 2 annotated in the genes CYB5B and PVRL4. Including covariates, we found 4 DMPs for symptoms variation, annotated in FAM20C, EPB41, OTUB1 and ADARB1, and 3 DMPs for response status, with 2 annotated in IQCE and FAM20C. Regional analysis revealed 54 differentially methylated regions (DMRs) with nominal p value area ≤ 0.05, with 9 presenting adjusted p-value area ≤ 0.10, annotated in MCF2L, SLC25A24, RUNX3, MIR637, FOXK2, FAM180B, POU6F1, ALS2CL and CCRL2. Considering covariates, we found 21 DMRs for symptoms variation and 26 DMRs for response (nominal p value area ≤ 0.05), with 4 presenting adjusted p-value area ≤ 0.10 for response, annotated in SNORD34, NLRP6, GALNT2 and SFT2D3. None remained significant after false discovery rate correction. Notably, ADARB1 variants are associated with suicide attempt in patients with psychiatric disorders, and SLC25A24 relates to conduct disorder. Several DMPs and DMRs are annotated in genes associated with inflammatory/immune processes. Longitudinal analyses on females (n = 22) revealed statistically significant DMRs (adjusted p value area ≤ 0.05) and trend-significant DMRs (adjusted p value area ≤ 0.07) for symptoms variation and response status, annotated in genes related to psychiatric disorders (ZFP57, POLD4, TRIM10, GAS7, ADORA2A, TOLLIP), trauma exposure (RIPOR2) and inflammatory/immune responses (LAT, DLX4, POLD4, FAM30A, H19). Pathway analysis on females revealed enrichment for transcriptional activity, growth factors, DNA maintenance, and immune pathways including IRF7 and IRF2. CONCLUSION: Although no significant results were found for the whole cohort, the study provides insights into ECT-associated methylation changes, highlighting DMPs and DMRs related to ECT outcomes. Analyses on females revealed significant DMRs and pathways related to psychiatric disorders and inflammatory/immune processes.

Exploring the potential of drug repurposing for treating depression.

Researchers are interested in drug repurposing or drug repositioning of existing pharmaceuticals because of rising costs and slower rates of new medication development. Other investigations that authorized these treatments used data from experimental research and off-label drug use. More research into the causes of depression could lead to more effective pharmaceutical repurposing efforts. In addition to the loss of neurotransmitters like serotonin and adrenaline, inflammation, inadequate blood flow, and neurotoxins are now thought to be plausible mechanisms. Because of these other mechanisms, repurposing drugs has resulted for treatment-resistant depression. This chapter focuses on therapeutic alternatives and their effectiveness in drug repositioning. Atypical antipsychotics, central nervous system stimulants, and neurotransmitter antagonists have investigated for possible repurposing. Nonetheless, extensive research is required to ensure their formulation, effectiveness, and regulatory compliance.

The association between ketamine and esketamine and suicidality: reports to the Food And Drug Administration Adverse Event Reporting System (FAERS).

INTRODUCTION: Replicated evidence indicates that ketamine and esketamine reduce measures of suicidality in persons with treatment-resistant depression (TRD). It remains uncertain whether individuals experience worsening of preexisting suicidality with either agent. RESEARCH DESIGN AND METHODS: The Food and Drug Administration Adverse Event Reporting System (FAERS) database was searched from 1970 and 2019 to 30 September 2023 for reports of suicidal ideation, depression suicidal, suicidal behavior, suicidal attempt, and completed suicide in association with ketamine and esketamine exposure, respectively. We present reporting odds ratios (ROR) significance was determined when the lower limit of the 95% confidence interval (CI) exceeded 1.0. Lithium was used as the control agent. RESULTS: Observed a higher ROR for suicidal ideation (ROR 7.58, 95% CI 6.34-9.07) and depression suicidal (ROR 14.19, 95% CI 1.80-112.07) with esketamine. Significantly lower RORs were observed for suicide attempt with ketamine (ROR 0.15, 95% CI 0.11-0.21) and esketamine (ROR 0.57, 95% CI 0.48-0.67). CONCLUSIONS: Mixed RORs across aspects of suicidality were observed with ketamine and esketamine. Limitations of the FAERS database prevent any determination of causal effects new onset suicidality to either agent. The lower RORs for suicide attempt with ketamine and esketamine is noted but cannot be interpreted as a direct therapeutic effect.

Technical Report: Efficacy and Safety of Low-Intensity Transcranial Magnetic Stimulation in the Remission of Depressive Symptoms in Patients With Treatment-Resistant Depression in Mexico.

Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that induces action potentials in the stimulated cortical area and has been approved by the Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The prevalence of MDD in Mexico almost tripled after the COVID-19 pandemic. In this study, we evaluated the safety and therapeutic effects of low-intensity TMS (Li-TMS) - characterized by inducing electric currents below the action potential threshold on the cerebral cortex - in 41 subjects diagnosed with treatment-resistant depression (TRD). A Li-TMS device dispensed repetitive magnetic pulses at 30 mT for 60 minutes during 20 sessions (once daily from Monday to Saturday) with the theta burst pattern. Our results suggest that Li-TMS is a safe therapy with antidepressant effects, demonstrated by the decrease in Beck Depression Inventory (BDI) scores and lessening of depressive symptoms.

Very Low-Dose Sublingual Ketamine for Borderline Personality Disorder and Treatment-Resistant Depression.

Borderline personality disorder (BPD) and treatment-resistant depression (TRD) are common mental disorders that are challenging to treat. Ketamine is an N-methyl-D-aspartate receptor antagonist that has shown promise as a rapid-acting antidepressant when administered intravenously. BPD symptoms have also been demonstrated to improve with repeated intravenous administration of ketamine, and a single case report described improvement in BPD following the intranasal administration of esketamine. We present a case report of a woman with BPD and TRD who responded to treatment with very low-dose sublingual ketamine. Very low-dose sublingual ketamine may be effective for the treatment of psychiatric disorders such as BPD and/or comorbid TRD.

Depression with comorbid borderline personality disorder - could ketamine be a treatment catalyst?

Borderline personality disorder (BPD) is diagnosed in 10-30% of patients with major depressive disorder (MDD), and the frequency of MDD among individuals with BPD reaches over 80%. The comorbidity of MDD and BPD is associated with more severe depressive symptoms and functional impairment, higher risk of treatment resistance and increased suicidality. The effectiveness of ketamine usage in treatment resistant depression (TRD) has been demonstrated in numerous studies. In most of these studies, individuals with BPD were not excluded, thus given the high co-occurrence of these disorders, it is possible that the beneficial effects of ketamine also extend to the subpopulation with comorbid TRD and BPD. However, no protocols were developed that would account for comorbidity. Moreover, psychotherapeutic interventions, which may be crucial for achieving a lasting therapeutic effect in TRD and BPD comorbidity, were not included. In the article, we discuss the results of a small number of existing studies and case reports on the use of ketamine in depressive disorders with comorbid BPD. We elucidate how, at the molecular and brain network levels, ketamine can impact the neurobiology and symptoms of BPD. Furthermore, we explore whether ketamine-induced neuroplasticity, augmented by psychotherapy, could be of use in alleviating core BPD-related symptoms such as emotional dysregulation, self-identity disturbances and self-harming behaviors. We also discuss the potential of ketamine-assisted psychotherapy (KAP) in BPD treatment. As there is no standard approach to the application of ketamine or KAP in individuals with comorbid TRD and BPD, we consider further research in the field as imperative. The priorities should include development of dedicated protocols, distinguishing subpopulations that may benefit most from such treatment and investigating factors that may influence its effectiveness and safety.

The association between ketamine and esketamine with alcohol and substance misuse: Reports to the Food and Drug Administration adverse event reporting system (FAERS).

INTRODUCTION: Ketamine and esketamine have been proven to be effective in treating adults with treatment resistant depression (TRD). Preliminary evidence indicates that, when combined with behavioral and psychological interventions, both agents may offer benefits for individuals with substance use disorder (SUD) and alcohol use disorder (AUD). Notwithstanding, concerns have been raised as to whether either or both agents are associated with abuse and/or gateway activity. METHODS: Herein, we evaluate disproportionate reporting expressed as reporting odds ratios (ROR) for esketamine and ketamine. The outcomes of interest include alcohol problem, alcoholism, alcohol abuse, substance dependence, SUD, substance abuse, drug dependence, drug use disorder and drug abuse as codified by the Medical Dictionary for Regulatory Activities (MedDRA) within the FAERS. The IC025 values were significant for ketamine in cases of alcohol abuse (0.28), substance dependence (1.88), substance use disorder (0.996), substance abuse (0.61), drug dependence (0.56), drug use disorder (1.17) and drug abuse (1.22). Additionally, oxycontin showed significant IC025 values for substance dependence (0.067), substance use disorder (0.094), substance abuse (0.035), and drug dependence (0.27). RESULTS: We observed significant increases in the reporting odds ratios (RORs) for ketamine with respect to various outcomes: alcohol abuse (ROR 2.84, 95 % CI 1.53-5.28; p = 0.0010), substance dependence (ROR 18.72, 95 % CI 8.49-41.30; p ≤ 0.0001), SUD (ROR 11.40, 95 % CI 4.24-30.65; p ≤ 0.0001), substance abuse (ROR 2.29, 95 % CI 1.73-3.04; p ≤ 0.0001), drug dependence (ROR 1.99, 95 % CI 1.64-2.42; p ≤ 0.0001), drug use disorder (ROR 4.50, 2.94-6.88; p ≤ 0.0001) and drug abuse (ROR 3.72, 3.36-4.12; p ≤ 0.0001). For esketamine, we observed that the ROR was significantly reduced for substance abuse (ROR 0.37, 95 % CI 0.22-0.63; p = 0.0003), drug dependence (ROR 0.13, 95 % CI 0.076-0.23; p ≤ 0.0001) and drug abuse (ROR 0.048, 95 % CI 0.030-0.078; p ≤ 0.0001). To our knowledge, this is the first report of spontaneous adverse events related to these outcomes of interest in the FAERS. CONCLUSION: Mixed RORs were observed across aspects of SUD and AUD for both ketamine and esketamine. Due to limitations in the FAERS, establishing causal links between new onset alcohol and substance misuse with either agent remains inconclusive. Possible beneficial effects on measures of SUD and AUD were observed. It is currently unclear, but possible, whether both agents have differential ameliorative effects across dimensions of SUD and AUD, which is a focus of ongoing research.

Emerging Outlook on Personalized Neuromodulation for Depression: Insights From Tractography-Based Targeting.

BACKGROUND: Deep brain stimulation has shown promise in treating individual patients with treatment-resistant depression, but larger-scale trials have been less successful. Here, we created what is, to our knowledge, the largest meta-analysis with individual patient data to date to explore whether the use of tractography enhances the efficacy of deep brain stimulation for treatment-resistant depression. METHODS: We systematically reviewed 1823 articles, selecting 32 that contributed data from 366 patients. We stratified the individual patient data based on stimulation target and use of tractography. Using 2-way type III analysis of variance, Welch's 2-sample t tests, and mixed-effects linear regression models, we evaluated changes in depression severity 1 year (9-15 months) postoperatively and at last follow-up (4 weeks to 8 years) as assessed by depression scales. RESULTS: Tractography was used for medial forebrain bundle (MFB) (n = 17 tractography/32 total), subcallosal cingulate (SCC) (n = 39 tractography/241 total), and ventral capsule/ventral striatum (n = 3 tractography/41 total) targets; it was not used for bed nucleus of stria terminalis (n = 11), lateral habenula (n = 10), and inferior thalamic peduncle (n = 1). Across all patients, tractography significantly improved mean depression scores at 1 year (p < .001) and last follow-up (p = .009). Within the target cohorts, tractography improved depression scores at 1 year for both MFB and SCC, though significance was met only at the α = 0.1 level (SCC: ß = 15.8%, p = .09; MFB: ß = 52.4%, p = .10). Within the tractography cohort, patients with MFB tractography showed greater improvement than patients with SCC tractography (72.42 ± 7.17% vs. 54.78 ± 4.08%) at 1 year (p = .044). CONCLUSIONS: Our findings underscore the promise of tractography in deep brain stimulation for treatment-resistant depression as a method for personalization of therapy, supporting its inclusion in future trials.

Perspectives in treatment-resistant depression: esketamine and electroconvulsive therapy.

Modern electroconvulsive therapy (ECT) and the approval of nasal esketamine for clinical use have significantly improved the approach to treatment-resistant depression (TRD), which is defined as non-response to at least two different courses of antidepressants with verified adherence to treatment, adequate dosage, and duration of treatment. The goal of this literature review is to present the newest evidence regarding efficacy and safety. Furthermore, we aim to provide an overview of future perspectives in this field of research, for example, regarding structural and molecular effects. Both treatment methods will be critically evaluated for their individual advantages, disadvantages, and response rates. Firstly, we will discuss the well-established method of ECT and its different treatment modalities. Secondly, we will discuss the properties of ketamine, the discovery of its antidepressive effects and the route to clinical approval of the esketamine nasal spray. We will comment on research settings which have evaluated intravenous ketamine against ECT. The decision-making process between esketamine nasal spray or ECT should include the assessment of contraindications, age, severity of disease, presence of psychotic symptoms, patient preference and treatment accessibility. We conclude that both treatment options are highly effective in TRD. If both are indicated, pragmatically esketamine will be chosen before ECT; however, ECT studies in ketamine non-responders are missing.

A Comparison of the Efficacy and Adverse Effects of Ketamine and Electroconvulsive Therapy in the Management of Treatment-Resistant Depression: A Systematic Review.

Ketamine has been repeatedly demonstrated to be an effective treatment in the management of patients with treatment-resistant depression (TRD). An important question is whether it is equally or more effective than the current gold standard of electroconvulsive therapy (ECT), as the adverse effects of ECT can lead to memory loss and neurocognitive deficits. A literature search was conducted for trials that directly compared the efficacy and adverse effects of ketamine and ECT via PubMed and Google Scholar. A total of 56 articles were identified with six included in this review. The studies included differed significantly in their quality and with differing levels of potential for bias. Ketamine has a more immediate effect when compared to ECT, but the antidepressant effects are shorter-lasting. Cognitive deficits were less pronounced in patients undergoing ketamine therapy. Many studies had a small number of participants and varied widely in the type of ECT used. Allocation bias seems likely in nonrandomized studies. Follow-up times were also short in some studies. The existing literature does not provide sufficient evidence to support the usage of ketamine over that of ECT for TRD, as remission rates were significantly higher over extended periods in ECT groups. Cognitive adverse effects were more pronounced in patients undergoing ECT. More high-quality randomized controlled trials (RCTs) directly comparing these two treatment modalities are required before drawing any firm conclusions.

Exploring the multifaceted potential of (R)-ketamine beyond antidepressant applications.

(R, S)- and (S)-ketamine have made significant progress in the treatment of treatment-resistant depression (TRD) and have become a research focus in recent years. However, they both have risks of psychomimetic effects, dissociative effects, and abuse liability, which limit their clinical use. Recent preclinical and clinical studies have shown that (R)-ketamine has a more efficient and lasting antidepressant effect with fewer side effects compared to (R, S)- and (S)-ketamine. However, a recent small-sample randomized controlled trial found that although (R)-ketamine has a lower incidence of adverse reactions in adult TRD treatment, its antidepressant efficacy is not superior to the placebo group, indicating its antidepressant advantage still needs further verification and clarification. Moreover, an increasing body of research suggests that (R)-ketamine might also have significant applications in the prevention and treatment of medical fields or diseases such as cognitive disorders, perioperative anesthesia, ischemic stroke, Parkinson's disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This article briefly reviews the mechanism of action and research on antidepressants related to (R)-ketamine, fully revealing its application potential and development prospects, and providing some references and assistance for subsequent expanded research.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.