Oral Ketamine Research Articles

The efficacy of oral ketamine in severely depressed patients at high risk of suicide.

Ketamine is most easily and inexpensively administered by the oral route and in racemic form. Oral racemic ketamine may be an important approach to the emergency management of suicide risk in clinical settings, especially in third world countries, that have a limited range of available healthcare resources. In a prospective, uncontrolled, open-label investigation, we studied 30 severely depressed inpatients who consented to participate in a pilot hospital service offering ketamine for management of high suicide risk. Patients sipped a solution of racemic ketamine (150mg) across 10-15min in 3 alternate day sessions. Patients were assessed using the Modified Scale for Suicidal Ideation (MSSI), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Improvement-Severity (CGI-S) scale at baseline and 1day after the last ketamine session. There was statistically and clinically significant improvement on all outcomes. Mean (standard deviation) MSSI scores dropped from 25.1(1.8) to 17.3(5.6), MADRS scores from 28.8(3.4) to 21.9(3.6), and CGI-S scores from 6.0(0.2) to 3.6(0.9). At endpoint, MSSI scores had dropped from severe to low or mild-to-moderate in 67% of patients. The 90 ketamine sessions were uneventful; the treatment was well tolerated and no patient dropped out. Oral racemic ketamine may be a useful and potentially life-saving approach to the emergency management of severely depressed patients at high risk of suicide.

Non-opioid analgesics for procedural pain in neonates.

Non-opioid analgesics for procedural pain in neonates.

Oral Ketamine or Nasal Midazolam for Sedation in Pediatric Upper Gastrointestinal Endoscopy

Background: There is no agreement on the route of administration and the drug of choice for providing adequate sedation for pediatric invasive procedures. Objectives: We compared the utility, safety, and sedation effects of intranasal midazolam and oral ketamine. Materials & Methods: This double-blind clinical trial was performed on 100 children aged 2 to 14 years who were candidates for upper gastrointestinal (GI) endoscopy. Patients were randomly assigned to two groups: ketamine (4 mg/kg orally) and midazolam (0.1 mg/ kg intranasal). Sedation score, fear levels, children’s behavior at the time of separation from parents, and vital signs were recorded. Results: Higher systolic blood pressure was seen in children who received ketamine (P=0.012) and lower arterial oxygen saturation in the midazolam group (P=0.023). Also, the level of sedation showed no significant difference between the groups. Conclusion: Based on the results, administering oral ketamine or intranasal midazolam before endoscopy induced a similar sedation score in children. Also, both methods could be safe and non-invasive modalities for sedation.

COMPARATIVE EVALUATION OF MIDAZOLAM AND KETAMINE WITH MIDAZOLAM ALONE AS ORAL PREMEDICATION IN CHILDREN”

Introduction: The main aims of preanesthetic medication in children are to reduce anxiety associated with the unfamiliar environment, facilitate the separation of the child from their parent and allow smooth induction of an-esthesia. Both oral midazolam and oral ketamine fulfil many of these char-acteristics and are useful. Method: As 48 patients of ASA grade 1 and 2, aged between 2-10 years un-dergoing elective surgery were allocated to one of two study groups using random numbers: Group 1 received midazolam 0.5mg/kg and group 2 re-ceived midazolam 0.25 mg/kg with ketamine 3 mg/kg. The medications were prepared and mixed with 25% dextrose up to a maximum volume of 0.3 ml/kg. Result: Uniform and acceptable sedation scores were seen in both the groups, without any serious side effects. However, the combination offered significantly more children in an awake, calm and quiet state, who were eas-ily separated from their parents. The induction scores, Recovery room characteristics and time to achieve satisfactory Aldrete score were also comparable between the two groups. Conclusion: Oral midazolam alone and a combination of midazolam with ketamine provide equally effective anxiolysis and separation characteristics. However, the combination provided more Benefits.

Treatment response with ketamine in chronic suicidality: An open label functional connectivity study

BackgroundKetamine has recently been proposed as a treatment option for suicidality. Whilst its mechanism of action has been explored at molecular levels, the effect on the brain at the organ level remains unclear. Here we investigate immediate post-treatment and prolonged large-scale resting-state neural network changes to elucidate the neuronal underpinnings associated with ketamine's therapeutic effects. MethodsTwenty-eight adults (aged 22–72 years) participated in the Oral Ketamine Trial On Suicidality, which is an open-label trial of weekly sub-anaesthetic doses of oral ketamine over 6 weeks. MRI was acquired at baseline, post-treatment, and follow-up. Functional connectivity changes at post-treatment and follow-up were examined using seed based and independent component analysis. ResultsThe seed-based connectivity analysis revealed significantly reduced connectivity at post-treatment from the right hippocampus to both right and left superior frontal gyrus, from the left anterior parahippocampus to right superior frontal gyrus, left superior frontal gyrus, right middle frontal gyrus, and left frontal operculum cortex. Compared with baseline, the ICA showed reduced anterior default mode network connectivities to bilateral posterior cingulate cortex, middle and anterior cingulate cortex, lingual gyrus, and cuneus and increased connectivity of the frontoparietal network to the right superior parietal lobule at post-treatment. LimitationsOpen label pilot study. ConclusionsWe have shown sub-anaesthetic doses of ketamine alters connectivity in networks which have been shown to be aberrantly hyper-connected in numerous psychiatric conditions. These neurocircuitry changes are supported by significant reductions in suicide ideation. Our results provide support for the use of ketamine as a treatment for suicidality.

Chronic oral ketamine prevents anhedonia and alters neuronal activation in the lateral habenula and nucleus accumbens in rats under chronic unpredictable mild stress

Acute injections of ketamine lead to rapid but transient antidepressant effects. Chronic oral treatment at low doses, a promising non-invasive alternative, may prolong this therapeutic effect. Here, we examine the antidepressant effects of chronic oral ketamine in rats under chronic unpredictable mild stress (CUMS), and reveal their neuronal correlates. Male Wistar rats were divided into control, ketamine, CUMS, and CUMS-ketamine groups. The CUMS protocol was applied to the latter two groups for 9 weeks, and ketamine (0.013 mg/ml) was provided ad libitum to the ketamine and CUMS-ketamine groups for 5 weeks. The sucrose consumption test, forced swim test, open field test, elevated plus maze, and Morris water maze were respectively used to assess anhedonia, behavioral despair, general locomotor activity, anxiety-like behavior and spatial reference memory. CUMS caused a reduction of sucrose consumption and impaired spatial memory, accompanied by increased neuronal activation in the lateral habenula (LHb) and paraventricular thalamic nucleus (PVT). Oral ketamine prevented behavioral despair and CUMS-induced anhedonia. Reward-triggered c-Fos immunoreactivity was decreased in the LHb and increased in the nucleus accumbens shell (NAcSh) in the CUMS-ketamine group compared to the CUMS group. Ketamine did not produce a differential effect in the OFT, EPM and MWM. These results show that chronic oral ketamine at low doses prevents anhedonia without impairing spatial reference memory. The observed neuronal activation changes in the LHb and NAcSh may be involved in the preventive effects of ketamine on anhedonia.This article is part of the Special Issue on “Ketamine and its Metabolites”.

Spectral Changes of EEG Following a 6-Week Low-Dose Oral Ketamine Treatment in Adults With Major Depressive Disorder and Chronic Suicidality.

Ketamine has considerable therapeutic potential in alleviating major depressive disorder and chronic suicidality. However, the clinical diagnosis of neuropsychiatric disorders requires more robust diagnostic criteria. Electroencephalography (EEG) has shown promise in classifying depressive and suicidal patients from healthy individuals. The present study aimed to identify changes in the spectral properties of EEG in patients with major depressive disorder and chronic suicidality after completing the 6-week Oral Ketamine Trial on Suicidality with follow-up occurring 4 weeks after final ketamine treatment and determine associations between EEG spectral output and clinical symptoms. Participants (n = 25) had 4-minute eyes closed resting state EEG recorded at frontal, temporal, centro-parietal, and occipital regions. Spectral analysis was performed with Welch's power spectrum density method, and the power of 4 distinct frequency bands was analyzed: theta, alpha, low-beta, and high-beta. Correlation analyses between changes in clinical symptoms and spectral power were conducted using Spearman's ranked correlation. Between pre- and posttreatment, only centro-parietal alpha power decreased. Between posttreatment and follow-up, centro-parietal alpha increased again in addition to increases in temporal alpha, centro-parietal and temporal theta, and occipital low-beta and decreases in occipital theta and temporal low-beta. Additionally, the decrease of occipital theta positively correlated with clinical subscales for depression and stress. EEG spectral analysis revealed significant changes in theta, alpha, and low-beta frequency bands. Alpha band showed initial changes after treatment; however, this trended back toward baseline levels after the treatment cessation. In contrast, theta and low-beta showed significant power changes only after the treatment had ended.

Sedative Agents in Minor Paediatric Oral Surgical ProceduresA Narrative Review

Sedation in pediatric dentistry reduces anxiety during surgical procedures and also helps cope with very stressful events encountered during dental treatment. Various sedative agents like Nitrous oxide, diazepam, midazolam, Ketamine, propofol, fentanyl, and dexmedetomidine have been administered through several sedation routes including oral, nasal, inhalation, intramuscular, and sub-mucosal to attain active sedation. However, it is evident that the sesedative drugs also have the prospective to causelethal complications. Aim: The present review was carried out to brief the clinical aspects of various sedative agents currently available in pediatric practices based on the existing literature with special emphasis on their role in minor pediatric oral surgical procedures. Discussion: Nitrous oxide is frequently used in combination with complextime-consuming procedures and dental extractions, particularly for young and anxious patients undergoing orthodontic extractions. Fentanyl decreases pain and anxiety but causes respiratory distress. Oral ketamine is a potent dissociative drug often combined with midazolam produces excellent analgesic and sedative effects. None the less, the most common combinations include sedatives with ketamine/opioids or dexmedetomidine to maintain the airway reflexes if given in small doses with precautions. Sometimes a combination of inhaled gases especially short-acting sevoflurane along with Diazepam is favored. Conclusion: Within the limitation, it is evident that a clear understanding of the proper selection of sedative agents, awareness of the intended level of sedation or route of drug administration, and knowledge of adverse responses during and after sedation are essential to achieve appropriate sedation levels during minor oral surgical procedures.

Oral ketamine as treatment for post-traumatic stress disorder: a case report

Oral ketamine as treatment for post-traumatic stress disorder: a case report

Oral Ketamine as a Premedication in Children Undergoing Day-Case Non-Invasive Procedures

Oral Ketamine as a Premedication in Children Undergoing Day-Case Non-Invasive Procedures

A Comparison of the Anti-Anxiety Effects of Oral Ketamine and Fluvoxamine in Children with Separation Anxiety Disorder Manifesting as School Refusal.

Children suffer from a high prevalence of anxiety problems that require prompt treatment. It has been demonstrated that ketamine offers rapid anti-anxiety effects. This study aimed to evaluate ketamine's anti-anxiety impact in the treatment of children with school-refusal separation anxiety disorder. In this open-labeled randomized clinical trial, 71 children (6-10 years) diagnosed with school refusal separation anxiety disorder were randomly assigned to two groups; a case group, who received ketamine at a weekly rising dose of 0.1 to 1 mg/kg; the control group treated with Fluvoxamine (25 mg/day), which could increase to 200 mg/day if necessary. The SCARED and CATS questionnaires were used to assess anxiety before treatment, at the 8th and 16th weeks of intervention. The data were analyzed using repeated-measures analysis of covariance. The mean anxiety scores in the eighth week (19.7 ± 16.1) were significantly lower in the ketamine group than before (31.5 ± 10.8). Until the sixteenth week (19.4 ± 14.6), there was no further decrease in scores in the ketamine group, in the fluvoxamine group, pre-treatment scores (36.3 ± 16.5) and eighth week (36.9 ± 16.6) were not significantly different, but scores decreased significantly in a sixteenth week (26.2 ± 12.5). In first eight weeks of treatment, ketamine was more successful than fluvoxamine at reducing anxiety disorder, considering the emergence of this disorder and the lack of major adverse effects of ketamine, it seems to be beneficial in early phases of treatment. Due to the quick onset of ketamine in future trials, their combination therapy is recommended during the initial weeks of treatment.

Electrophysiological phenotypes of suicidality predict prolonged response to oral ketamine treatment

Oral ketamine has shown to be a rapid-acting antidepressant and a potential treatment option for suicidality, however, repeated doses are often required. Objective markers of prolonged treatment response are needed to help individuals and clinicians make informed treatment decisions. This secondary analysis sought to identify objective electrophysiological predictors of both prolonged response and dose sensitivity to low-dose oral ketamine in people with chronic suicidality. Individuals with a Beck Scale for Suicide Ideation total score (BSS) ≥ 6 (N = 29) completed a six-week ketamine treatment, pre-treatment electroencephalography and follow-up assessment of suicidality (four weeks from the final ketamine dose). Prolonged response was observed in 52% of participants (follow-up BSS reduced by 50% or ≤6); nearly half were prolonged non-responders. There was decisive evidence for a predictive Bayesian linear regression model with follow-up BSS score as the response variable and pre-treatment auditory evoked power bands as predictors (theta, alpha and beta frequencies, BF10 = 17,948, R2 = 0.70). A Bayesian one-way ANOVA indicated strong evidence for a model of positive association between auditory evoked power and ketamine dose sensitivity (theta-alpha BF+0 = 108, effect size δ = 1.3, 95% CI 0.5–2.1; high-beta BF+0 = 7.4, δ = 0.8, 95% CI 0.1–1.6). Given auditory evoked power may index serotonin neurotransmission, these results suggest that a prolonged response to ketamine may, in part, be mediated by pre-treatment serotonergic functioning. In addition, the observed beta power differences may arise from GABAergic functioning. These suicidality phenotypes, identifiable by pre-treatment electrophysiology, may aid diagnosis, treatment selection and prediction of prolonged treatment outcome.

Procedural sedation in children for fractionated radiation treatment: Intranasal dexmedetomidine versus oral midazolam and ketamine.

Sedation in paediatric cancer for fractionated radiation treatment (RT) is unique as the child has to be still for accurate delivery of RT, monitoring of the child is from a remote location and sedation is repeated for multiple sessions of RT. The present study was undertaken to compare the efficacy of intranasal dexmedetomidine with oral midazolam and ketamine combination for repeated sedation during fractionated RT in paediatric oncology. Ninety children aged between 3-6 years, planned for 21 fractions of RT, were randomised to receive intranasal dexmedetomidine 2 μg/kg (group D) or oral midazolam 0.2 mg/kg and ketamine 5 mg/kg (group MK). The 21 sessions of fractionated radiotherapy were divided into three subgroups of seven consecutive exposures 1-7, 8-14 and 15-21 for comparison. The primary endpoint was to determine the incidence of successful sedation. The sedation score achieved, time to satisfactory sedation and discharge, rescue ketamine required, and side effects were secondary endpoints. The incidence of successful sedation in the three successive RT subgroups; sessions: 1-7, 8-14 and 15-21, was 82%, 75.6% and 66.7% in group D, as compared to 40%, 24.4% and 13.3% in group MK, respectively. (P < 0.001). A decrease in successful sedation was noted in the successive subgroups. Time to successful sedation and discharge was earlier in group D in comparison to MK (P = 0.000). More patients in group MK required rescue ketamine (P = 000). Intranasal dexmedetomidine produces more satisfactory sedation as compared to oral ketamine with midazolam for fractionated RT.

Comparison between oral midazolam versus oral ketamine plus midazolam as preanesthetic medication in autism spectrum disorder: double-blind randomized clinical trial

BackgroundConventional dental care is often impossible in patients with Autism Spectrum Disorder (ASD). Non-collaborative behaviors, sometimes associated with aggressiveness, are usual justifications for premedication in this population. Thereby, this research focuses on the effects of oral midazolam versus oral ketamine plus midazolam as preanesthetic medication in ASD. MethodsThe sample included 64 persons with ASD, aged 2˗59 years, scheduled for dental care under general anesthesia. The primary objective of this study was to compare degrees of sedation between two parallel, double-blinded, equally proportional groups randomized to receive oral midazolam (0.5 mg.kg−1, maximum 15 mg) or oral midazolam (0.5 mg.kg−1) associated with oral S(+)-ketamine (3 mg.kg−1, maximum 300 mg). The secondary outcomes were the need of physical stabilization to obtain intravenous line, awakening time, and occurrence of adverse events. ResultsAccording to the dichotomous analysis of sedation level (Ramsay score 1 and 2 versus Ramsay ≥ 3), oral association of S(+)-ketamine and midazolam improved sedation, with increased probability of Ramsay ≥ 3, Relative Risk (RR) = 3.2 (95% Confidence Interval [95% CI] = 1.32 to 7.76) compared to midazolam alone. Combined treatment also made it easier to obtain venous access without physical stabilization, RR = 2.05 (95% CI = 1.14 to 3.68). There were no differences between groups regarding awakening time and the occurrence of adverse events. ConclusionThe association of oral S(+)-ketamine with midazolam provides better preanesthetic sedation rates than midazolam alone and facilitates intravenous line access in patients with autism.

Efficacy and safety of low dose oral ketamine for controlling pain and distress during intravenous cannulation in children: a double-blind, randomized, placebo-controlled trial.

BackgroundKetamine is widely used in infants and young children for procedural sedation and anesthesia. The aim of this study was to evaluate the efficacy and safety of low dose oral ketamine to control pain and distress in children during intravenous (IV) cannulation.MethodsThis is a prospective, randomized, double-blind study, including children aged between 3 and 6 years requiring a non-emergent IV-line placement. Children were randomly assigned to two groups, treated either with oral ketamine or a placebo. All patients were monitored for vital signs. Pain was assessed using the Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wong-Baker Faces Pain Rating Scale (WBFS) scales and sedation using a 5-point sedation score. The facility of IV-line placement was measured by a 3-point scale. Adverse effects were recorded after 1 and 24 hours.ResultsA total of 79 and 81 children were entered in the ketamine and placebo groups, respectively. The heart and respiratory rates increased significantly in the placebo group. The median CHEOPS 4 (95% confidence interval [CI] 3, 4, P < 0.001) and WBFS 6 (95% CI 4, 6, P < 0.001) scores decreased statistically in the ketamine group. IV-line placement was 50% easier in the ketamine group (95% CI 37%, 63%, P < 0.001). No serious adverse effects were observed in all cases.ConclusionsLow dose oral ketamine effectively decreased the pain and distress during IV cannulation in children without any significant adverse reactions.

Analgesic Efficacy of Oral Aspirin/Ketamine Combination for Management of Acute Musculoskeletal Pain in the Emergency Department – A Proof of Concept Pilot Study

BackgroundMusculoskeletal pain (MSK) affects one out of three adults and is the most common source of significant long-term pain, physical disability, and under-treatment in the emergency department (ED). ObjectiveWe aimed to assess the analgesic efficacy of a combination of oral VTS-Aspirin® (Vitalis Analgesics, New York, NY) and ketamine in managing acute MSK pain in adult ED patients. MethodsThis was a prospective, proof-of-concept, single-arm, pilot study evaluating the analgesic efficacy of a single dose of oral combination of VTS-Aspirin and ketamine in adult ED patients with acute moderate-to-severe MSK pain. The primary outcome included the difference in pain scores on an 11-point numeric pain rating scale at 60 min. Secondary outcomes included the need for rescue analgesia, the occurrence of adverse events at 60 min, and a change in pain scores at 120 min. ResultsWe enrolled 25 subjects in the study. The mean baseline pain score was 8.6 and the mean pain score at 60 min decreased to 4.8. The oral ketamine dose ranged from 24 mg to 50 mg, with a mean dose of 37.8 mg. No clinically concerning changes in vital signs were noted. No serious adverse events occurred in any of the subjects. Majority of adverse effects were transient and weak in intensity. ConclusionWe demonstrated that administration of an oral combination of VTS-Aspirin and ketamine to adult ED patients with acute MSK pain resulted in clinically significant pain relief in 80% of enrolled subjects.

Oral Aspirin/ketamine versus oral ketamine for emergency department patients with acute musculoskeletal pain

ObjectiveThe purpose of this study is to investigate if an orally administered combination of aspirin and ketamine will provide better analgesia than a ketamine alone in adult patients presenting to the Emergency Department (ED) with acute musculoskeletal pain. MethodsWe conducted a prospective, randomized, open-label trial of ED patients aged 18 and older presenting with moderate to severe acute musculoskeletal pain as defined by an 11-point numeric rating scale (NRS) with an initial score of ≥5. Patients were randomized to receive either 324 mg of VTS-Aspirin™ and 0.5 mg/kg of oral ketamine (AOK) that is directly swallowed or 0.5 mg/kg of oral ketamine (OK) alone that is swished first and then swallowed. Patients were assessed at baseline, 30, 60, 90, and 120 min. The primary outcome was a difference in pain scores between the two groups at 60 min post-administration. Secondary outcomes included adverse events and the need for rescue analgesia. ResultsWe enrolled 60 patients in the study (30 per group). The difference in mean pain scores at 60 min between the AOK and OK groups was 2.6 [95% CI: 1.38–3.77] showing a lower mean pain score in the OK group. At 60 min, the AOK group had a change in mean pain score from 8.4 to 6.3 (difference 2.1; 95% CI: 1.35–3.00). The OK group had a change in mean pain score from 7.8 to 3.7 (difference 4.1, 95% CI: 3.25–4.90). No clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. The most commonly reported adverse effects were dizziness and fatigue. None of the participants required rescue analgesia at 60 min post-medications administration. ConclusionThe administration of an oral combination of VTS-Aspirin ™ and ketamine resulted in less analgesia compared to oral ketamine alone, for the short-term treatment of moderate to severe acute musculoskeletal pain in the ED.Clinicaltrials.govRegistration: NCT04860804

Esketamine inhaled as dry powder: Pharmacokinetic, pharmacodynamic and safety assessment in a preclinical study

Ketamine and its enantiomer esketamine have gained much attention in recent years as potent, fast-acting agents for the management of treatment-resistant depression. However, an alternative to oral ketamine administration is required to ensure adequate systemic exposure as the drug undergoes extensive first-pass metabolism. We propose dry powder inhalation as a new esketamine delivery route. Here, we examine the pharmacokinetics, pharmacodynamics, toxicology and safety of this novel esketamine administration method. Esketamine (10 mg/kg) and ketamine racemate (20 mg/kg) were administered to rats by dry powder inhalation, intravenous injection or intratracheal instillation and the pharmacokinetics of these treatments were compared. Analyte concentration of ketamine stereoisomers and their metabolites was assessed by LC-MS/MS method. Esketamine showed a clinically relevant pharmacokinetic profile, with high bioavailability (62%) and relatively low maximum concentration peaks. Esketamine exhibited high penetration of the blood-brain barrier, but pharmacodynamic examinations of brain homogenates showed no changes in selected protein phosphorylation or expression analyzed by the immunoblotting method. We conducted GLP-compliant 14-day and 28-day general toxicity studies in rats and dogs, respectively, subjected to dry esketamine powder inhalation. The maximum daily dosages were 46.5 mg/kg and 36.5 mg/kg, respectively. We also performed pharmacological safety studies. Esketamine inhaled as dry powder had an expected safety profile consistent with its known pharmacological action. None of its observed effects were considered toxicologically significant. The pharmacological safety studies confirmed that the observed effects were transient and that inhaled esketamine had a good safety profile. Hence, our preclinical studies demonstrated that dry powder inhalation is a highly efficacious and safe delivery route for esketamine and may be a viable alternative administration route meriting further clinical development.

Ketamine for Adults With Treatment-Resistant Depression or Post-Traumatic Stress Disorder

&#x0D; Two randomized controlled trials reported mixed evidence on the efficacy of repeated IV ketamine infusions for improving post-traumatic stress disorder. One randomized controlled trial with small sample size found that repeated IV ketamine infusions significantly improved post-traumatic stress disorder symptoms compared with midazolam in civilian population, while the other randomized controlled trial with larger sample size could not demonstrate a significant efficacy on post-traumatic stress disorder symptoms compared with placebo in military population. The antidepressant effects of ketamine were rapid, but the effects were not sustained after few weeks of post-treatment follow-up.&#x0D; One randomized controlled trial comparing IV ketamine with IV esketamine found both treatments had comparable acute antidepressant effects for treatment-resistant depression 24 hours following infusion.&#x0D; Two randomized controlled trials provided mixed evidence on the efficacy of single infusion of IV ketamine that was used as anesthetic agent for electroconvulsive therapy for treatment-resistant depression. One randomized controlled trial involving military population showed that patients undergoing electroconvulsive therapy for treatment-resistant depression with ketamine anesthesia had similar improvement of depression when compared with patients undergoing electroconvulsive therapy with methohexital anesthesia. However, in other randomized controlled trial comparing with propofol-based anesthesia in a civilian population, ketamine-based anesthesia provided faster improvement in depressive symptoms and fewer electroconvulsive therapy treatments to achieve disease remission.&#x0D; In a small randomized controlled trial, alternate infusions of subanesthetic dose of ketamine or midazolam with alternate electroconvulsive therapy showed no significant difference in antidepressant effects between groups.&#x0D; The efficacy of oral ketamine was demonstrated in 1 randomized controlled trial that repeated administration of oral ketamine significantly reduced depressive symptoms compared with placebo.&#x0D; A small retrospective chart review study showed that repeated administration of intramuscular ketamine had no significant differences in the improvement of depressive and anxiety symptoms compared with repeated transcranial magnetic stimulation.&#x0D; Findings suggest overall safety and tolerability of ketamine for treatment of post-traumatic stress disorder or treatment-resistant depression. Most frequent side effects associated with ketamine were dissociative symptoms and cardiovascular changes such as increased blood pressure and heart rate, but these effects were transient.&#x0D; The Danish guideline recommend against the use of IV ketamine in patients with treatment-resistant depression, due to low quality and insufficient evidence regarding the lack of long-term efficacy and the risk of abuse of ketamine. Likewise, the Canadian guideline recommends IV ketamine be considered as third-line treatment for adults with TRD, because of the short-lived efficacy of ketamine, its side effects, and the lack of strategies for relapse prevention after ketamine infusions.&#x0D;

Risk Factors for the Development of Neuropsychiatric Adverse Effects in Ketamine-Treated Pain

Ketamine use has increased recently for the management of acute and chronic pain. Ketamine can cause a variety of neuropsychiatric adverse effects, such as hallucinations, dysphoria, and nightmares. The objective of this study was to explore risk factors for the development of neuropsychiatric adverse effects in ketamine-treated pain. This was a retrospective, single-center cohort study of hospitalized patients who received low dose intravenous (IV) ketamine or oral ketamine for pain. Patients who had a neuropsychiatric adverse effect were compared to those who did not. One hundred and seventy-one patients were included, with 155 receiving IV ketamine and 16 receiving oral ketamine. Overall, 50 (29.2%) had a neuropsychiatric adverse effect and 26 (15.2%) required treatment discontinuation. No significant differences were found between patients who tolerated ketamine and those who did not. Patients who had an adverse effect were numerically less likely to receive benzodiazepines (28% vs 39.7%, p = 0.153), as were patients who required discontinuation of ketamine (23.1% vs. 41.4%, p = 0.08). In patients receiving ketamine for pain, predicting who may be more likely to experience neuropsychiatric adverse effects remains difficult. Further research is warranted to determine whether benzodiazepines are safe and effective for mitigating these adverse effects in this setting.