Low-dose ketamine safely reduces acute pain in the ED with a more rapid and shorter effect than morphine.

SOURCE CITATION: Guo J, Zhao F, Bian J, et al. Low-dose ketamine versus morphine in the treatment of acute pain in the emergency department: a meta-analysis of 15 randomized controlled trials. Am J Emerg Med. 2024;76:140-149. 38071883.

British Association of Urological Surgeons Consensus statements on the management of ketamine uropathy.

OBJECTIVES: To provide guidance in the form of consensus statement in the management of ketamine uropathy. METHODS: A literature review of ketamine uropathy was performed. The consensus method was of a modified nominal group technique and has been use in the previous British Association of Urological Surgeons (BAUS) consensus documents and was led by the Female, Neurological and Urodynamic Urology Section of the BAUS. RESULTS: A number of consensus statements detailing the assessment and management of urological complications relate to the recreational use of ketamine (ketamine uropathy) in both elective and emergency urology settings. CONCLUSION: Comprehensive management pathway for ketamine-related urinary tract dysfunction and uropathy has been detailed.

Antinociceptive and adverse effects of morphine:ketamine mixtures in rats.

Prescription opioids are the gold standard for treating moderate to severe pain despite their well-documented adverse effects. Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. One strategy for improving the margin of safety of opioids is combining them with non-opioid drugs to decrease the opioid dose needed for pain relief, thereby reducing adverse effects that occur with larger doses. The N-methyl-D-aspartate receptor antagonist ketamine has been used safely as an analgesic but only under a very limited range of conditions. The current studies characterized the antinociceptive, behavioral suppressant, and gastrointestinal effects of morphine and ketamine alone and in mixtures to determine their interaction in 24 adult male Sprague-Dawley rats (n = 8 per assay). Given alone, both morphine and ketamine produced antinociception, decreased responding for food, and reduced gastrointestinal transit (i.e. produced constipation). The effects of morphine:ketamine mixtures generally were additive, except for the antinociceptive effects of 1:1 mixtures for which the difference in slope (i.e. non-parallel shift) between the observed and predicted effects suggested synergy at smaller doses and additivity at larger doses. The potency of morphine to produce constipation was not enhanced by administration of morphine:ketamine mixtures with antinociceptive effects. The nature of the interaction between morphine and ketamine for adverse effects such as dependence, withdrawal, abuse, or respiratory depression remains unknown but also might be related to the ratio of each drug in mixtures. It will be important to identify conditions that produce the largest potential therapeutic window in humans.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ketamine.

BACKGROUND: Ketamine, an arylcyclohexylamine dissociative anesthetic agent, has evolved into a versatile therapeutic. It has a rapid-onset, well-understood cardiovascular effects and a favorable safety profile in clinical use. Its enantiomeric compound, esketamine, was approved by the Food and Drug Administration in 2019 for both treatment-resistant depression and major depressive disorder with suicidal ideation. AREAS OF UNCERTAINTY: Research indicates dose-dependent impacts on cognition, particularly affecting episodic and working memory following both acute administration and chronic use, albeit temporarily for the former and potentially persistent for the latter. Alongside acute risks to cardiovascular stability, ketamine use poses potential liver toxicity concerns, especially with prolonged or repeated exposure within short time frames. The drug's association with "ketamine cystitis," characterized by bladder inflammation, adds to its profile of physiological risks. THERAPEUTIC ADVANCES: Data demonstrate a single intravenous infusion of ketamine exhibits antidepressant effects within hours (weighted effect size averages of depression scores (N = 518) following a single 0.5 mg/kg infusion of ketamine is d = 0.96 at 24 hours). Ketamine is also effective at reducing posttraumatic stress disorder (PTSD) symptom severity following repeated infusions (Clinician-Administered PTSD Scale scores: -11.88 points compared with midazolam control). Ketamine also decreased suicidal ideation in emergency settings (Scale for Suicidal Ideation scores: -4.96 compared with midazolam control). Through its opioid-sparing effect, ketamine has revolutionized postoperative pain management by reducing analgesic consumption and enhancing recovery. LIMITATIONS: Many studies indicate that ketamine's therapeutic effects may subside within weeks. Repeated administrations, given multiple times per week, are often required to sustain decreases in suicidality and depressive symptoms. CONCLUSIONS: Ketamine's comprehensive clinical profile, combined with its robust effects on depression, suicidal ideation, PTSD, chronic pain, and other psychiatric conditions, positions it as a substantial contender for transformative therapeutic application.

A systematic review and meta-analysis of the efficacy of ketamine and esketamine on suicidal ideation in treatment-resistant depression.

PURPOSE: To systematically assess the evidence of efficacy and safety of the use of ketamine and esketamine for patients with treatment-resistant depression (TRD) with suicidal ideation (SI). METHODS: We independently searched for clinical trials from inception to January 2023 using electronic databases, e.g., PubMed and EMBASE. A systematic review and meta-analysis were performed to assess SI scores of depression rating scales, which were regarded as the outcomes. RESULTS: A total of five independent double-blind, placebo controlled randomized clinical trials (RCTs) are eligible for inclusion. Four of the studies used ketamine as an intervention and one used esketamine as an intervention. Three hundred ninety-one patients with TRD were included (the intervention group with ketamine or esketamine is 246, and the control group is 145). No statistically significant interaction between the subscales of suicide ideation (SMD = - 0.66, 95% CI (- 1.61, 0.29); Z = 1.36, P = 0.17) and antidepressant effects (SMD = - 0.99, 95% CI (- 2.33, 0.34); Z = 1.46, P = 0.15) based on the results of ketamine and esketamine, compared with placebo groups. CONCLUSION: This meta-analysis suggested that esketamine and ketamine have failed to reduce suicidal ideation in patients with TRD. Further studies are desirable to confirm the effects of ketamine and esketamine in TRD patients.

Rethinking ketamine as a panacea: adverse effects on oxygenation and postoperative outcomes.

Ketamine is receiving renewed interest in perioperative medicine as an anaesthetic adjunct and a treatment for chronic conditions, including depression. Ketamine's complex pharmacologic profile results not only in several desirable effects, such as anaesthesia and analgesia, but also multiple adverse effects affecting the central nervous, cardiovascular, and respiratory systems. In addition to defining patient-centred outcomes in future clinical studies on the perioperative uses of ketamine, careful monitoring for its numerous adverse effects will be paramount.

A non-inferiority randomized controlled trial comparing nebulized ketamine to intravenous morphine for older adults in the emergency department with acute musculoskeletal pain.

OBJECTIVE: Our study aimed to investigate the analgesic efficacy of nebulized ketamine in managing acute moderate-to-severe musculoskeletal pain in older emergency department (ED) patients compared with intravenous (IV) morphine. METHODS: This was a non-inferiority, double-blind, randomized controlled trial conducted at a single medical centre. The patients aged 65 and older, who presented at the ED musculoskeletal pain within 7 days and had a pain score of 5 or more on an 11-point numeric rating scale (NRS), were included in the study. The outcomes were a comparison of the NRS reduction between nebulized ketamine and IV morphine 30 minutes after treatment, incidence of adverse events and rate of rescue therapy. RESULTS: The final study included 92 individuals, divided equally into two groups. At 30 minutes, the difference in mean NRS between the nebulized ketamine and IV morphine groups was insignificant (5.2 versus 5.7). The comparative mean difference in the NRS change from baseline between nebulized ketamine and IV morphine [-1.96 (95% confidence interval-CI: -2.45 to -1.46) and -2.15 (95% CI: -2.64 to -1.66) = 0.2 (95% CI: -0.49 to 0.89)] did not exceed the non-inferiority margin of 1.3. The rate of rescue therapy did not differ between the groups. The morphine group had considerably higher incidence of nausea than the control group (zero patients in the ketamine group versus eight patients (17.4%) in the morphine group; P = 0.006). CONCLUSIONS: Nebulized ketamine has non-inferior analgesic efficacy compared with IV morphine for acute musculoskeletal pain in older persons, with fewer adverse effects.

Challenges of acute pain management in older patients.

Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research.

Treatment of Brachioradial Pruritus: A Tertiary Center Retrospective Analysis.

This retrospective study investigates the efficacy of 2 treatment regimens, pregabalin alone versus pregabalin combined with ketamine, amitriptyline, and lidocaine cream, in reducing itch in patients with brachioradial pruritus at a tertiary care center. Electronic medical records of 64 brachioradial pruritus patients seen at the University of Miami Itch Center were analyzed. A significant reduction in itch scores was seen with both treatments, with no significant difference between the groups. A small number of patients experienced adverse effects, including drowsiness and weight gain with pregabalin and skin irritation with ketamine, amitriptyline, and lidocaine cream. Ultimately, our findings underscore the potential of utilizing combined therapy for difficult-to-treat brachioradial pruritus cases and implementing individualized approaches for managing neuropathic pruritus. Further controlled clinical trials are needed to establish optimal treatment protocols.

Ketamine cystitis following ketamine therapy for treatment-resistant depression - case report.

BACKGROUND: Ketamine is a novel and exciting putative antidepressant medication for patients with treatment-resistant depression. A complication commonly seen in frequent and heavy recreational use of ketamine is ulcerative cystitis, which presents with lower urinary tract symptoms (LUTS) and upper renal tract damage and can be seen in over 25% of regular users. Although Ketamine-induced cystitis (KIC) is a recognised complication in recreational use of ketamine, its occurrence in therapeutic use of ketamine in depression has so far not been reported. The exact pathogenesis of KIC is currently unknown, making treatment and prevention advice much more difficult. Early diagnosis of KIC and immediate cessation of ketamine has been shown to improve adverse urinary tract symptoms and prevent further damage. CASE PRESENTATION: We present a case of a 28-year-old female who was started on ketamine treatment for depression, and who then developed symptoms of KIC, which was confirmed by urine microscopy, culture and analysis. CONCLUSIONS: To our knowledge, this is the first reported case of KIC in a patient receiving treatment-dose ketamine as part of their antidepressant therapy.

The impact of depressive symptoms on cognitive impairments in chronic ketamine users.

BACKGROUND: Chronic ketamine use has been associated with cognitive impairments, while depressive symptoms are commonly observed in individuals using ketamine. However, the influence of depressive symptoms on cognitive impairments in chronic ketamine users remains unclear. This study aimed to examine the impact of depressive symptoms on cognitive function in this population. METHODS: A cross-sectional study was conducted with a sample of chronic ketamine users. Participants underwent comprehensive cognitive assessments, including measures of attention, executive function, working memory, verbal and visual memory. Depressive symptoms were assessed using Beck Depression Inventory (BDI) scores. Multivariate analyses were utilized to compare the cognitive performance of individuals who use ketamine, both with and without depressive symptoms, as well as a control group, while controlling for relevant covariates. RESULTS: The results revealed a significant negative impact of depressive symptoms on cognitive impairments, particularly in the domains of memory and executive function, among chronic ketamine users. The analysis of partial correlations revealed that among individuals who use ketamine and have depressive symptoms, those with higher levels of depressive symptoms demonstrated poorer cognitive performance compared to individuals with lower levels of depressive symptoms, controlling for potential confounding factors. CONCLUSIONS: The findings suggest that depressive symptoms contribute to cognitive impairments, specifically in memory and executive function, in chronic ketamine users. Therefore, it is crucial to evaluate depressive symptoms when considering cognitive enhancement treatment for this population.

Comparison of Fentanyl, Ketamine, and Lidocaine Combined with Propofol Anesthesia in Patients with Crohn Disease Undergoing Colonoscopy.

BACKGROUND Colonoscopy is the predominant invasive procedure for Crohn disease (CD) patients. Opioids and propofol carry risks of respiratory and cardiovascular complications. This study aimed to evaluate whether substituting fentanyl with ketamine or lidocaine could diminish propofol usage and minimize adverse events. MATERIAL AND METHODS In total, 146 patients with CD scheduled for elective colonoscopy were assigned to anesthesia with fentanyl (n=47), ketamine (n=47), or lidocaine (n=55). Propofol was administered to achieve sufficient anesthesia. Measured outcomes in each group included propofol consumption, hypotension and desaturation incidents, adverse event types, consciousness recovery time, abdominal pain intensity, Aldrete scale, and Post Anaesthetic Discharge Scoring System (PADSS). RESULTS Patients administered fentanyl needed significantly more propofol (P=0.017) than those on ketamine, with lidocaine showing no notable difference (P=0.28). Desaturation was significantly less common in the ketamine and lidocaine groups than fentanyl group (P<0.001). The ketamine group experienced milder reductions in mean arterial (P=0.018) and systolic blood pressure (P<0.001). Recovery metrics (Aldrete and PADSS scores) were lower for fentanyl (P<0.001), although satisfaction and pain levels were consistent across all groups (P=0.797). Dizziness occurred less frequently with lidocaine than fentanyl (17.2%, P=0.018) and ketamine (15.1%, P=0.019), while metallic taste incidents were more prevalent in the lidocaine group (13.5%, P=0.04) than fentanyl group. CONCLUSIONS Using ketamine or lidocaine instead of fentanyl in anesthesia for colonoscopy in patients with CD significantly lowers propofol use, reduces desaturation events, maintains blood pressure more effectively, without increasing hypotension risk, and accelerates recovery, without negatively impacting adverse events or patient satisfaction.

Efficacy and Safety of Ketamine-Dexmedetomidine Versus Ketamine-Propofol Combination for Periprocedural Sedation: A Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: The combination of ketamine with propofol and dexmedetomidine has gained popularity for sedation and general anesthesia in different populations. In our meta-nalysis, we helped the anesthesiologists to know the efficiency and the efficacy of both combinations in adult and pediatric patients. METHODS: We searched PubMed, CENTRAL, Web of Science, and Scopus from inception to August 1, 2023. Our outcome parameters for efficacy were recovery time, pain score, and physician satisfaction while for safety were the related cardiorespiratory, neurological, and gastrointestinal adverse events. RECENT FINDINGS: Twenty-two trials were included with a total of 1429 patients. We found a significantly longer recovery time in the ketadex group of 7.59 min (95% CI, 4.92, 10.26; I2 = 94%) and a significantly less pain score of - 0.72 (95% CI, - 1.10, - 0.34; I2 = 0%). Adults had a significantly better physician satisfaction score with the ketofol group, odds ratio of 0.29 (95% CI, 0.12, 0.71; I2 = 0%). Recovery agitations were higher in the ketofol group with an odds ratio of 0.48 (95% CI, 0.24, 0.98; I2 = 36%). Furthermore, we found a significant difference between the combinations with a higher incidence in the ketadex group with pooled odds ratio of 1.75 (95% CI, 1.06, 2.88; I2 = 15%). Ketadex was associated with lower pain scores, hypoxic events and airway obstruction, and emergence agitation. At the same time, ketofol had much more clinician satisfaction which might be attributed to the shorter recovery time and lower incidence of nausea and vomiting. Therefore, we suppose that ketadex is the better combination in periprocedural sedation for both adult and pediatric patients who are not at greater risk for postoperative nausea and vomiting.

Ketamine's love story with the heart: A Takotsubo twist.

INTRODUCTION: Ketamine is a dissociative anesthetic with N-methyl-d-aspartate and glutamate receptor antagonist properties. It has been the most popular agent to facilitate emergency department procedures for three decades. Considered a safe and effective option for procedural sedation, ketamine has rapid onset, short effective sedation time, and a low risk profile. Ketamine's sympathomimetic effects could theoretically induce stress-related cardiac dysfunction, including cardiomyopathy. A review of the literature demonstrates one prior report of stress (Takotsubo) cardiomyopathy after ketamine sedation. CASE REPORT: In this case report, we present a case of Takotsubo cardiomyopathy after ketamine sedation for distal radius fracture reduction. The patient presented hemodynamically normal with an unremarkable cardiac ultrasound and progressed to hypoxia from bilateral pulmonary edema, eventually requiring intubation. Inpatient evaluation revealed elevated high sensitivity troponin, non-obstructive coronary arteries on catheterization, and echocardiogram findings of Takotsubo cardiomyopathy. She received operative fixation of her radius fracture by orthopedics and was discharged home on hospital day 9. She had an unremarkable follow up with cardiology but had no echocardiogram to determine full resolution. CONCLUSION: Although ketamine has robust evidence of safety and efficacy, physicians should be aware of the potential complications of its sympathomimetic effects, from hypertension and tachycardia to overt Takotsubo cardiomyopathy.

Dexmedetomidine-ketamine combination versus fentanyl-midazolam for patient sedation during flexible bronchoscopy: a prospective, single-blind, randomized controlled trial.

BACKGROUND: Sedation during flexible bronchoscopy (FB) should maintain an adequate respiratory drive, ensure maximum comfort for the patient, and warrant that the objectives of the procedure are achieved. Nevertheless, the optimal sedation method for FB has yet to be established. This study aimed to compare the standard recommended combination of midazolam-fentanyl (MF) with that of dexmedetomidine-ketamine (DK) for patient sedation during FB. METHODS: Patients subjected to FB were randomly assigned to a DK (n = 25) and an MF group (n = 25). The primary outcome was the rate of critical desaturation events (arterial oxygen saturation < 80% with nasal oxygen supply 2 L/min). Secondary outcomes included sedation depth, hemodynamic complications, adverse events, and patient and bronchoscopist satisfaction. RESULTS: The incidence rates of critical desaturation events were similar between the two groups (DK: 12% vs. MF: 28%, p = 0.289). DK achieved deeper maximum sedation levels (higher Ramsay - lower Riker scale; p < 0.001) and was associated with longer recovery times (p < 0.001). Both groups had comparable rates of hemodynamic and other complications. Patient satisfaction was similar between the two groups, but bronchoscopist satisfaction was higher with the DK combination (p = 0.033). CONCLUSION: DK demonstrated a good safety profile in patients subjected to FB and achieved more profound sedation and better bronchoscopist satisfaction than the standard MF combination without increasing the rate of adverse events.

Enhancing Safety in Tumescent Liposuction: Managing Sedation-Related Respiratory Issues and Serious Complications Under Deep Sedation with the Propofol-Ketamine Protocol.

BACKGROUND: Over the past 4 years, aesthetic surgery, notably liposuction, has substantially increased. Tumescent liposuction, a popular technique, has two variants-true tumescent liposuction (TTL) and semi-tumescent liposuction. While TTL reduces risks, it has limitations. There is no literature reported on semi-tumescent liposuction under deep sedation using the propofol-ketamine protocol, which is proposed as a potentially safe alternative. METHODS: The retrospective analysis covered 8 years and included 3094 patients performed for tumescent liposuction under deep sedation, utilizing the propofol-ketamine protocol. The evaluation of patient safety involved an examination of potential adverse events with a specific focus on respiratory issues related to sedation, including instances of mask ventilation. RESULTS: Among the 3094 cases, no fatalities were recorded. Noteworthy events included 43 mask ventilation instances, primarily occurring in the initial 10 min. Twelve cases experienced surgery cancellation due to various factors, including respiratory issues. Three patients were transferred to upper-level hospitals, while another three required blood transfusions. Vigilant management prevented significant complications, and other adverse events like venous thromboembolism (VTE), fat embolism, severe lidocaine toxicity, and so on were not observed. CONCLUSIONS: The analysis of 3094 tumescent liposuction cases highlighted the overall safety profile of the propofol-ketamine protocol under deep sedation. The scarcity of severe complications underscores its viability. The study emphasizes the significance of thorough preoperative assessments, careful patient selection, and awareness of potential complications. Prompt interventions, particularly in addressing sedation-related respiratory issues, further contribute to positive outcomes for patients. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Do Microplastics Have Neurological Implications in Relation to Schizophrenia Zebrafish Models? A Brain Immunohistochemistry, Neurotoxicity Assessment, and Oxidative Stress Analysis.

The effects of exposure to environmental pollutants on neurological processes are of increasing concern due to their potential to induce oxidative stress and neurotoxicity. Considering that many industries are currently using different types of plastics as raw materials, packaging, or distribution pipes, microplastics (MPs) have become one of the biggest threats to the environment and human health. These consequences have led to the need to raise the awareness regarding MPs negative neurological effects and implication in neuropsychiatric pathologies, such as schizophrenia. The study aims to use three zebrafish models of schizophrenia obtained by exposure to ketamine (Ket), methionine (Met), and their combination to investigate the effects of MP exposure on various nervous system structures and the possible interactions with oxidative stress. The results showed that MPs can interact with ketamine and methionine, increasing the severity and frequency of optic tectum lesions, while co-exposure (MP+Met+Ket) resulted in attenuated effects. Regarding oxidative status, we found that all exposure formulations led to oxidative stress, changes in antioxidant defense mechanisms, or compensatory responses to oxidative damage. Met exposure induced structural changes such as necrosis and edema, while paradoxically activating periventricular cell proliferation. Taken together, these findings highlight the complex interplay between environmental pollutants and neurotoxicants in modulating neurotoxicity.

[Ketamin: a harmful recreational drug]. / Kétamine : une substance récréative qui fait mal.

Adolescence is a developmental phase that exposes young people to exploratory behaviors, including substance abuse. In Switzerland, recreational ketamine use among young people is on the rise and is likely to lead to irreversible somatic complications. Primary care physicians play an essential role in identifying ketamine users, and should offer brief interventions, risk-reduction advice and a psychosocial assessment of the situation, involving close relatives. In the event of secondary damage, particularly urological damage, coordinated management by specialists is essential to achieve symptom regression. Primary and secondary prevention measures are also essential in the fight against addiction among young people.

L'adolescence est une phase développementale exposant les jeunes à des comportements exploratoires, dont la prise de substances. En Suisse, la consommation récréative de kétamine chez les jeunes est en augmentation et est susceptible d'entraîner des complications somatiques irréversibles. Le médecin de premier recours joue un rôle essentiel dans l'identification des usager-e-s de kétamine et doit proposer des interventions brèves, des conseils de réduction des risques et une évaluation globale de la situation (anamnèse psychosociale), en impliquant les proches. En cas d'atteinte secondaire, en particulier urologique, une prise en charge coordonnée entre spécialistes est primordiale pour viser une régression des symptômes. Des mesures de prévention primaires et secondaires sont également essentielles dans la lutte contre les addictions chez les jeunes.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.