Ketamine In Treatment-resistant Depression Research Articles

Interventional approaches to treatment resistant depression (DTR) in children and adolescents: A systematic review and meta-analysis

BackgroundMajor depressive disorder (MDD) is highly prevalent in youth. Conventional treatment paradigms primarily involve selective serotonin reuptake inhibitors (SSRIs) and psychotherapy, yet a significant proportion of this population exhibits treatment-resistant depression (TRD). In adults, interventional therapies like Electroconvulsive Therapy (ECT), repetitive Transcranial Magnetic Stimulation (rTMS), and ketamine have shown promise for TRD, but their comparative efficacy remains underexplored in Adolescent and pediatric population. This systematic review and meta-analysis aims to assess the relative effectiveness of ECT, rTMS, and ketamine in treating TRD among adolescents. MethodsFollowing PRISMA guidelines, we systematically searched databases for studies of ECT, rTMS, or ketamine for treatment-resistant depression in youth ages 10–24. Three reviewers independently screened for inclusion based on predefined criteria. Included observational and randomized controlled trials reported depression symptoms with measures like HDRS and MADRS in youth treated with ECT, rTMS, or ketamine. Two reviewers extracted data on interventions, patients, and depression symptom outcomes. Chance-adjusted inter-reviewer agreement was calculated. For meta-analysis, we pooled standardized mean differences (SMDs) in depression scores using random effects models and assessed heterogeneity with I2 statistics. ResultsMeta-analysis of 10 observational studies examined SMD in depression scores for treatment resistant depression patients treated with ECT, ketamine, or rTMS. Patients treated with ECT had a significantly lower SMD of 1.99 (95 % CI 0.92–3.05, p < 0.001) compared to baseline. Patients treated with ketamine also had a significantly lower SMD of 1.58 (95 % CI 1.04–2.12, p < 0.001). Patients treated with rTMS had the lowest SMD of 2.79 (95 % CI 0.79–4.80, p = 0.006). There was no significant difference between the three groups overall (p > 0.05). Comparative analysis between ECT and ketamine found no significant difference in SMD (p = 0.387). Comparison of ECT versus rTMS found a significant difference in SMD favoring rTMS (p = 0.004). Comparison of ketamine versus rTMS suggested a potential difference in SMD favoring rTMS (p = 0.058). In summary, rTMS resulted in significantly larger reductions in depression scores than ECT, and potentially larger reductions than ketamine. ConclusionsThis meta-analysis illustrates the ability of rTMS, ECT, and ketamine to improve depression in youth. rTMS resulted in the largest improvements, highlighting its potential as a first-line treatment for pediatric treatment-resistant depression given its favorable side effect profile compared to ECT. Further research directly comparing these modalities is needed.

A randomised, open-label, pragmatic pilot comparison of oral and intravenous ketamine in treatment-resistant depression

BackgroundFor depression, ketamine is more conveniently administered by oral than by intravenous (iv) routes. The relative antidepressant efficacy of oral vs iv ketamine is unknown. ObjectivesTo assess the acute efficacy and the persistence of improvement with open-label oral versus iv ketamine in outpatients with treatment-resistant depression (TRD). MethodsAdults with TRD were randomized to oral (N=30) or IV (N=31) ketamine. Oral ketamine was dosed at 150 mg in 50 mL of water, sipped across 15 min. IV ketamine was dosed at 0.5 mg/kg, infused across 40 min. Ketamine sessions (total, 7) were administered on alternate days for 2 weeks. Ongoing antidepressant drugs were continued unchanged. Patients were assessed at baseline, day 14, and day 30. The primary outcome was the endpoint Hamilton Rating Scale for Depression score on day 14. Secondary outcomes were endpoint scores on the Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, and Clinical Global Impression-Severity of Illness and Improvement. ResultsOverall dropout was lower with oral than with iv ketamine (26.7 % vs 54.8 %; P=0.03). The 2 groups did not differ in depression ratings and in response and remission rates on all instruments on both days 14 and 30. Adverse events such as headache (56.7 % vs 74.2 %) and drowsiness (0.0 % vs 22.6 %) were less common with oral ketamine. ConclusionIn TRD outpatients treated in general hospitals, oral ketamine maybe better accepted and tolerated than iv ketamine. Conclusions about relative efficacy cannot be drawn because of the high dropout rate with iv ketamine.

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 objectiveof this study is toevaluate 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.

Ketamine in treatment-resistant depression

Ketamine in treatment-resistant depression

Improvement in depressive symptoms in a patient with severe and enduring anorexia nervosa and comorbid major depressive disorder using psychotherapy-assisted IV ketamine : a case report

Background Anorexia nervosa is a life-threatening psychiatric illness with a high mortality rate and limited treatment options. This illness is frequently comorbid with major depressive disorder, leading to additional obstacles in patient quality of life, and increasing the mortality rate further due to risk of suicide. Ketamine, a competitive N-methyl-D-aspartate receptor antagonist, has been shown to be beneficial in depression given its effects on neuroplasticity. There are few cases in the literature describing ketamine use in patients with eating disorders, and even fewer that describe psychotherapy-assisted ketamine use in this patient population. We present the case of a 33-year-old woman with a history of severe and enduring anorexia nervosa and comorbid major depressive disorder who we treated safely with ketamine-assisted psychotherapy using intravenous ketamine in a general hospital setting.Case presentationOur patient is a 33-year-old woman with past psychiatric history of severe and enduring anorexia nervosa and major depressive disorder with comorbid psychiatric and medical conditions who presented to the hospital due to malnutrition. She had an extensive psychiatric history as well as multiple medical hospitalizations due to her eating disorder. She had tried numerous psychiatric treatments, including antidepressants, mood stabilizers, antipsychotics, electroconvulsive therapy, and multiple types of therapies without significant improvement in symptoms. She agreed to try ketamine for treatment-resistant depression and received it intravenously for seven sessions in a closely monitored setting, and simultaneously engaged in acceptance and commitment therapy during sessions. She demonstrated increased cognitive flexibility, disappearance of suicidal ideation, and reduction in Beck Depression Inventory Scores.ConclusionsOur case is unique in that it demonstrates the successful usage of ketamine-assisted psychotherapy in a hospital setting with severe and enduring anorexia nervosa and comorbid major depressive disorder. Her body mass index was profoundly low at 13, whereas the lowest documented in the literature was 16.9. This case shows that ketamine-assisted psychotherapy may be a promising treatment modality for patients with anorexia nervosa with co-morbid depression who have failed other interventions.

Ketamine in Treatment-Resistant Depression

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has antidepressant and antisuicidal effects, as shown by multiple studies done over the past two decades, that can be used effectively in the management of treatment-resistant depression (TRD). The United States Food and Drug Administration has approved intranasal (S)-ketamine in combination with an oral antidepressant for TRD. Although research is promising with respect to ketamine's effect on depression and suicidality, the need for in-office administration and treatment monitoring limits the accessibility of treatment. Significant concerns remain regarding the risks of treatment and its abuse potential. Nonetheless, its potential efficacy in TRD and suicidality makes ketamine an effective treatment modality for this patient population. [ Psychiatr Ann . 2024;54(6):e170–e176.]

241. Efficacy of Ketamine in Treatment-Resistant Depression: An Umbrella Review

241. Efficacy of Ketamine in Treatment-Resistant Depression: An Umbrella Review

Guidelines for ketamine use in clinical psychiatry practice.

In this editorial, we emphasise the efficacy and challenges of using ketamine in treatment-resistant depression. We highlight the need for comprehensive evidence-based guidelines to manage the use of both licensed and off-licence ketamine formulations and discuss recent efforts by Beaglehole et al to develop ketamine guidelines in New Zealand. We finally advocate for national registries to monitor ketamine therapy, ensuring its responsible and effective use in the management of depression.

An Umbrella Review of Effectiveness of Intravenous Ketamine in Treatment-Resistant Depression

IntroductionMajor depressive disorder (MDD) is a tremendous global disease burden and the leading cause of disability worldwide. Unfortunately, individuals diagnosed with MDD typically experience a delayed response to traditional antidepressants and many do not adequately respond to pharmacotherapy, even after multiple trials. The critical need for novel antidepressant treatments has led to a recent resurgence in the clinical application of psychedelics, and intravenous ketamine, which has been investigated as a rapid-acting treatment for treatment resistant depression (TRD) as well acute suicidal ideation and behavior. However, variations in the type and quality of experimental design as well as a range of treatment outcomes in clinical trials of ketamine make interpretation of this large body of literature challenging.ObjectivesThis umbrella review aims to advance our understanding of the effectiveness of intravenous ketamine as a pharmacotherapy for TRD by providing a systematic, quantitative, large-scale synthesis of the empirical literature.MethodsWe performed a comprehensive PubMed search for peer-reviewed meta-analyses of primary studies of intravenous ketamine used in the treatment of TRD. Meta-analysis and primary studies were then screened by two independent coding teams according to pre-established inclusion criteria as well as PRISMA and METRICS guidelines. We then employed metaumbrella, a statistical package developed in R, to perform effect size calculations and conversions as well as statistical tests.ResultsIn a large-scale analysis of 1,182 participants across 51 primary studies, repeated-dose administration of intravenous ketamine demonstrated statistically significant effects (p&lt;0.05) compared to placebo-controlled as well as other experimental conditions in patients with TRD, as measured by standardized clinician-administered and self-report depression symptom severity scales.ConclusionsThis study provides large-scale, quantitative support for the effectiveness of intravenous, repeated-dose ketamine as a therapy for TRD and a report of the relative effectiveness of several treatment parameters across a large and rapidly growing literature. Future investigations should use similar analytic tools to examine evidence-stratified conditions and the comparative effectiveness of other routes of administration and treatment schedules as well as the moderating influence of other clinical and demographic variables on the effectiveness of ketamine on TRD and suicidal ideation and behavior.Disclosure of InterestNone Declared

Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation – Clinical and safety results

IntroductionWe investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. Material and methodsPatients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. ResultsTwenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01).Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DiscussionOur results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Metabolomic biomarkers for (R, S)-ketamine and (S)-ketamine in treatment-resistant depression and healthy controls: A systematic review.

Ketamine is increasingly used for treatment-resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs). A comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine. A total of 1859 abstracts were screened of which 11 were included for full-text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open-label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment-resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post-infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients. This systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed.

Use of ketamine for treatment resistant depression: updated review of literature and practical applications to a community ketamine program in Edmonton, Alberta, Canada.

Though intravenous (IV) ketamine and intranasal (IN) esketamine are noted to be efficacious for treatment-resistant depression (TRD), access to each of these treatments within healthcare systems is limited due to cost, availability, and/or monitoring requirements. IV ketamine has been offered at two public hospital sites in Edmonton, Canada since 2015. Since then, demand for maintenance ketamine treatments has grown. This has required creative solutions for safe, accessible, evidence-based patient care. Aims of this paper are twofold. First, we will provide a synthesis of current knowledge with regards to the clinical use of ketamine for TRD. Consideration will be given regarding; off-label racemic ketamine uses versus FDA-approved intranasal esketamine, populations treated, inclusion/exclusion criteria, dosing, assessing clinical response, concomitant medications, and tolerability/safety. Second, this paper will describe our experience as a community case study in applying evidence-based treatment. We will describe application of the literature review to our clinical programming, and in particular focus on cost-effective maintenance treatments, long-term safety concerns, routes of ketamine administration other than via intravenous, and cautious prescribing of ketamine outside of clinically monitored settings. We conducted a literature review of the on the use of ketamine for TRD up to June 30, 2023. Key findings are reviewed, and we describe their application to our ketamine program. Evidence for the use of ketamine in resistant depression has grown in recent years, with evolving data to support and direct its clinical use. There is an increasing body of evidence to guide judicious use of ketamine in various clinical circumstances, for a population of patients with a high burden of suffering and morbidity. While large-scale, randomized controlled trials, comparative studies, and longer-term treatment outcomes is lacking, this community case study illustrates that currently available evidence can be applied to real-world clinical settings with complex patients. As cost is often a significant barrier to accessing initial and/or maintenance IV or esketamine treatments, public ketamine programs may incorporate SL or IN ketamine to support a sustainable and accessible treatment model. Three of such models are described.

Predicting treatment response to ketamine in treatment-resistant depression using auditory mismatch negativity: Study protocol.

Ketamine has recently attracted considerable attention for its rapid effects on patients with major depressive disorder, including treatment-resistant depression (TRD). Despite ketamine's promising results in treating depression, a significant number of patients do not respond to the treatment, and predicting who will benefit remains a challenge. Although its antidepressant effects are known to be linked to its action as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, the precise mechanisms that determine why some patients respond and others do not are still unclear. This study aims to understand the computational mechanisms underlying changes in the auditory mismatch negativity (MMN) response following treatment with intravenous ketamine. Moreover, we aim to link the computational mechanisms to their underlying neural causes and use the parameters of the neurocomputational model to make individual treatment predictions. This is a prospective study of 30 patients with TRD who are undergoing intravenous ketamine therapy. Prior to 3 out of 4 ketamine infusions, EEG will be recorded while patients complete the auditory MMN task. Depression, suicidality, and anxiety will be assessed throughout the study and a week after the last ketamine infusion. To translate the effects of ketamine on the MMN to computational mechanisms, we will model changes in the auditory MMN using the hierarchical Gaussian filter, a hierarchical Bayesian model. Furthermore, we will employ a conductance-based neural mass model of the electrophysiological data to link these computational mechanisms to their neural causes. The findings of this study may improve understanding of the mechanisms underlying response and resistance to ketamine treatment in patients with TRD. The parameters obtained from fitting computational models to EEG recordings may facilitate single-patient treatment predictions, which could provide clinically useful prognostic information. Clinicaltrials.gov NCT05464264. Registered June 24, 2022.

Ketamine for Treatment-Resistant Depression and Suicidality in Adolescents: An Observational Study of 3 Cases.

Ketamine for Treatment-Resistant Depression and Suicidality in Adolescents: An Observational Study of 3 Cases.

516. Metabolomic Biomarkers for (R, S)-Ketamine and (S)-Ketamine in Treatment-Resistant Depression and Healthy Controls: A Systematic Review

516. Metabolomic Biomarkers for (R, S)-Ketamine and (S)-Ketamine in Treatment-Resistant Depression and Healthy Controls: A Systematic Review

A Pain Physician and Anesthesiologist’s Perspective on Ketamine for Treatment-Resistant Depression

A Pain Physician and Anesthesiologist’s Perspective on Ketamine for Treatment-Resistant Depression

Registered clinical trials investigating ketamine and esketamine for treatment-resistant depression: A systematic review

AbstractBackground and AimsKetamine and esketamine have garnered interest in both psychiatric research and clinical practice for treatment-resistant depression (TRD). In this review, we examined registered trials investigating the therapeutic use of ketamine or esketamine for TRD, with the aim of characterizing emerging trends and knowledge gaps.MethodsThe ClinicalTrials.gov electronic registry and results database was queried from inception to February 5, 2022, adhering to elements of the PRISMA guideline, we evaluated trial eligibility in the qualitative synthesis. Data regarding study design, drug regimens, and measures were subsequently abstracted and descriptively analyzed.ResultsThe search returned 86 records, of which 56 trials were included in the final review. The number of trials investigating ketamine and esketamine for TRD increased since 2008, with higher peaks observed in 2015 (n = 9) and 2021 (n = 9). Most trials were Phase 2 (13, 23.2%) or Phase 3 (11, 19.6%), gathering preliminary data on efficacy and/or further data on safety and efficacy with variant dosing and pharmacological approaches. By and large, trials examined ketamine and esketamine as individual versus combination treatments (45% and 25%, respectively). The Montgomery-Asberg Depression Rating Scale (MADRS) was most commonly used to assess clinical outcomes (75%).ConclusionsThere are increasingly large-scale and late-phase trials of esketamine over ketamine for TRD, coupled with efforts to centralize evidence on these medications. Yet several trials do not assess patient characteristics that may affect treatment response, such as age, sex, and race. By understanding these design limitations, scientists and clinicians can avoid research waste and funding bodies can judiciously direct support towards high priority research.

Antidepressant and anti-suicidal effects of ketamine in treatment-resistant depression associated with psychiatric and personality comorbidities: A double-blind randomized trial

ObjectiveTo evaluate the effects of ketamine treatment on depression and suicidal ideation in treatment resistant depression (TRD) and to determine whether they are influenced by other psychiatric and personality comorbidities. MethodsA randomized double-blind parallel-arm controlled study on 36 patients with TRD. Patients were divided into two treatment groups: ketamine (K group) and placebo (P group). Patients in the K and P groups received one infusion of medicine per week for two weeks. All participants were assessed using the Structured Interview for the Five-Factor Personality Model (SIFFM), Hamilton Depression Rating Scale (HDRS), Suicide Probability Scale (SPS), and Symptom Checklist 90 (SCL 90). ResultsAfter treatment, there was a significant decrease in the total HDRS and SPS scores in the K group compared to the P group, but the magnitude of response was not influenced by the presence of other psychiatric symptoms. Regression model, only receive ketamine treatment was significant factor for improve suicide and depression scores. Limitationslack of data on other outcomes that are important to patients (e.g., quality of life, cognition) and need for a larger sample size. ConclusionsKetamine infusions in TRD reduce suicidal ideation and depression despite the presence other psychiatric and personality disorders.

Practical use of compounded sublingual and intranasal ketamine for treatment resistant depression: a community case report in edmonton, alberta, canada

Practical use of compounded sublingual and intranasal ketamine for treatment resistant depression: a community case report in edmonton, alberta, canada

A survey of drug liking and cravings in patients using sublingual or intranasal ketamine for treatment resistant depression: A preliminary evaluation of real world addictive potential.

Ketamine has gained rapid popularity as a treatment option for treatment resistant depression (TRD). Though seen only in limited contexts, ketamine is a potential drug of abuse, addiction and diversion. Clinical ketamine studies to date have not systematically evaluated factors relevant to addiction risk in patients with TRD, but in treating patients with ketamine, risks of potential harms related to addiction must be considered. As clinical access to intravenous ketamine programs is limited in much of Canada, these considerations become even more important for clinicians who elect to offer patients less supervised, non-parenteral forms of ketamine treatment. This study explores factors relevant to addiction risk in a real-world sample of 33 patients with TRD currently or previously treated with sublingual (SL) or intranasal (IN) ketamine in the community. First, patients were surveyed using a Drug Liking and Craving Questionnaire (DLCQ) to assess their level of drug liking and craving for ketamine, and to screen for symptoms of a ketamine use disorder. Second, the pharmacy records of these patients were reviewed for red flags for addiction such as dose escalation or early refills. Third, surveys were administered to the treating psychiatrists of patients who had discontinued ketamine to determine if abuse concerns contributed to reason for discontinuation. Though limited to a small sample, results indicate that ketamine is not a universally liked or craved substance in patients with TRD. Prescribers of non-parenteral ketamine should monitor patients and prescribe cautiously. Factors related to addiction (as in the DLCQ) should be explored for clinicians to consider individual risk/benefit for judicious use of ketamine in patients with TRD.