•Esketamine 0.25 mg/kg was noninferior to ketamine 0.5 mg/kg in promoting remission of major depression symptoms 24 h after a single intravenous administration in subjects with treatment-resistant ...depression.•Esketamine and ketamine demonstrated a similar safety pattern and were well tolerated by most participants.•This is the first head-to-head randomized clinical trial comparing racemic ketamine and esketamine in patients with treatment-resistant depression.
Ketamine and its enantiomers have recently been highlighted as one of the most effective therapeutic options in refractory depression. However, racemic ketamine and esketamine have not been directly compared. The aim of this study is to assess the efficacy and safety of esketamine compared to ketamine in patients with treatment-resistant depression (TRD).
This is a randomized, double-blind, active-controlled, bicentre, non-inferiority clinical trial, with two parallel groups. Participants were randomly assigned to a 40-min single intravenous infusion of ketamine 0.5 mg/kg or esketamine 0.25 mg/kg. The primary outcome was the difference in remission rates for depression 24 h following intervention using the Montgomery-Åsberg Depression Rating Scale (MADRS), with a non-inferiority margin of 20%.
63 subjects were included and randomly assigned (29 to receive ketamine and 34 to receive esketamine). At 24 h, 24.1% of participants in the ketamine group and 29.4% of participants in the esketamine group showed remission, with a difference of 5.3% (95% CILB -13.6%), confirming non-inferiority. MADRS scores improved from 33 (SD 9.3) to 16.2 (SD 10.7) in the ketamine group and from 33 (SD 5.3) to 17.5 (SD 12.2) in the esketamine one, with a difference of -5.27% (95% CILB, -13.6). Both groups presented similar mild side effects.
Esketamine was non-inferior to ketamine for TRD 24 h following infusion. Both treatments were effective, safe, and well tolerated.
Registered in Japan Primary Registries Network: UMIN000032355.
We aimed to analyze the efficacy and safety of arketamine, the
R
(−)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD ...received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points CI 95% 13.6–27.0;
p
< 0.001; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.
Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one ...open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo.
This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model.
Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal.
This was a pilot study with a small sample and underpowered.
Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations.
•0.5 mg/kg arketamine was not superior to placebo in our TRD sample (n = 10).•Arketamine did not evoke meaningful dissociative symptoms or other adverse events.•There was a significant carryover effect with a 1-week interval crossover design.•This is the first RCT on arketamine's efficacy and safety in TRD patients.•Further studies with increasing doses and multiple administrations may be needed.
Dissociative symptoms are common, possibly severe, side effects associated with the use of ketamine and esketamine in depression. We investigated the relationship between trait dissociation and ...dissociation induced by ketamine and esketamine used as augmentation therapy in treatment-resistant depression (TRD). Adults with TRD were randomly assigned to receive a single intravenous infusion, with a duration of 40 min, of either esketamine 0.25 mg/kg or ketamine 0.5 mg/kg. We assessed trait dissociation with the Dissociative Experience Scale (DES) and, to evaluate induced dissociation, the Clinician-Administered Dissociative States Scale (CADSS) was used. Thirty-two subjects received esketamine and 29 received ketamine. The groups had similar median DES scores (p = 0.26). More than 30% of the patients in both groups had DES scores ≥30 points. The median CADSS score in the esketamine group was equivalent to that in the ketamine group (p = 0.40). Every 5 points increment in the DES was associated with a 10.9% (95% CI 4.5–17.8%) increase in the CADSS, in an exponential fashion when the two groups were pooled together. Subjects with high trait dissociation had a higher risk of induced dissociation state (relative risk RR 1.41, 95% CI 1.11–1.78) and very high induced dissociation (RR 3.05, 95% CI 1.14–8.15). Induced dissociation was not a serious adverse effect. The findings suggest that trait dissociation is a predictor of induced dissociation by Ketamine or Esketamine in TRD subjects. Screening for trait dissociation and counseling patients with high trait dissociation on the risks of dissociation by these drugs are recommended.
•Trait dissociation values were similar among ketamine and esketamine groups.•More than 30% of patients in both groups had high levels of trait dissociation.•Daily dissociation experiences correlated to dissociation induced by both drugs.•High trait dissociation subjects had a higher risk of induced dissociation.•Induced dissociation was not reported as a serious effect.
There are significantly fewer options for the treatment of bipolar depression than major depressive disorder, with an urgent need for alternative therapies. In this pilot study, we treated six ...subjects with bipolar disorder types I and II (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) who had been in a current depressive episode for at least four weeks. Four subjects were female (66.66%), and the mean age was 45.33 (±12.32). Subjects received adjunct treatment with two arketamine intravenous infusions one week apart—0.5 mg/kg first and then 1 mg/kg. The mean baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score was 36.66, which decreased to 27.83 24h after the first infusion of 0.5 mg/kg of arketamine (p = 0.036). In respect of the 1 mg/kg dose, the mean MADRS total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p < 0.001). Arketamine appears to have rapid-acting antidepressant properties, consistent with previous animal studies on major depression. All individuals tolerated both doses, exhibiting nearly absent dissociation, and no manic symptoms. To the best of our knowledge, this pilot trial is the first to test the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) for bipolar depression.
•The mean MADRS total score prior to the infusion of 0.5 mg/kg of arketamine was 36.66, which dropped to 27.83 after 24h (p = 0.036).•The mean MADRS total score prior to a 1 mg/kg arketamine infusion was 32.0, which fell to 17.66 after 24h (p < 0.001).•The mean MADRS item 10 score prior to the infusion of 0.5 mg/kg of arketamine was 3.33, which dropped to 1.33 after 24h (p = 0.006).•There were no severe adverse effects reported for either dose, dissociation was nearly absent, and no manic symptoms were reported.•Further randomized, crossover, active placebo-controlled clinical trials with larger samples and longer follow-ups should be performed.
Masonry has been widely used as a construction method. However, there is a lack of information on its fire behavior due to the multitude of variables that could influence this method. This paper ...aimed to identify the influence of loading and mortar coating thickness on the fire behavior of masonry. Hence, six masonries made of clay tiles laid with mortar were evaluated. The mortar coating had a thickness of 25 mm on the face not exposed to high temperatures, while the fire-exposed face had thicknesses of 0, 15, and 25 mm. For each mortar coating thickness, two specimens were tested, with and without loading of 10 tf/m. The real-scale specimens were subjected to the standard ISO 834 fire curve for four hours, during which the properties of stability, airtightness, and thermal insulation were assessed. Results showed that loaded specimens yielded smaller deformations than unloaded ones. Samples that lacked mortar coating on the fire-exposed face underwent fire resistance decrease of 27.5%, while the ones with 15 mm decreased by 58.1%, and the ones with 25 mm decreased by 41.0%. As mortar coating thickness increased, the plane deformations decreased from 40 mm to 29 mm and the thermal insulation properties of the walls improved significantly. For specimens with mortar coating thickness of 25 mm, the load application resulted in a reduction of 23.8% of the thermal insulation, while the unloaded specimen showed a decrease of 43.3%, as well as a modification of its fire-resistance rating.
Converging evidence supports the role of the glutamate, an excitatory amino acid neurotransmitter, in the pathophysiology of obsessive-compulsive disorder (OCD). Ketamine and esketamine, both ...noncompetitive N -methyl- d -aspartate antagonists, have emerged as a promising medication for this psychiatric disorder, given its possible efficacy with faster onset and good tolerability. The purpose of this retrospective chart review is to evaluate whether unbiased clinical documentation supports formal clinical trials of esketamine for an OCD indication.
A retrospective chart review of patients with treatment-resistant OCD receiving a single dose of esketamine (0.5mg/kg) added to standard therapy was conducted. The Yale-Brown Obsessive-Compulsive Scale and the Montgomery-Åsberg Depression Rating Scale were used to evaluate OCD and depressive symptoms respectively at baseline, 24 hours, and 7 days after esketamine administration. Descriptive statistics were used to analyze the data.
Eight subjects were identified in this retrospective chart review: esketamine was administered subcutaneously in 7 and intravenously in 1. One week after infusion, 25% of the sample met criteria for treatment response and 50% for partial response. Major depressive disorder was a comorbid diagnosis in 75% of the sample and 2 of these subjects showed a positive antidepressant response.
Our findings provide preliminary evidence that esketamine may reduce obsessive-compulsive symptoms in a subset of treatment-resistant OCD patients.
Abstract Purposes/Background The aims of the study were to assess subanesthetic esketamine as an antidepressant for major depressive disorder with psychotic features (PMDD) and to compare ...posttreatment symptoms among those with PMDD to a sample of nonpsychotic depression (major depressive disorder MDD). Methods/Procedures This study is a retrospective chart review of patients with major depression and current psychotic symptoms, treated with a single parenteral 0.5-mg/kg dose of esketamine. Depression symptoms were assessed at baseline and 24-hour posttreatment with the Montgomery-Åsberg Depression Rating Scale. Individuals with PMDD were matched in a 1:2 ratio to nonpsychotic MDD patients from a randomized, noninferiority clinical trial of esketamine. Findings/Results A total of 15 individuals with PMDD were included, which had higher baseline depression scores (PMDD = 40.9, MDD = 33.6, P = 0.004). A statistically significant change in depressive symptoms was found for the PMDD sample (β = −16.20 95% confidence interval, −23.30 to −9.10, P < 0.001), and no difference between PMDD and MDD groups was observed in the matched-sample analysis (β = −2.2 95% confidence interval, −9.32 to 4.58, P = 0.537). Treatment-induced dissociative symptoms were present for both groups, self-contained to within 2 hours after treatment, and no exacerbation of psychotic symptoms was found in clinical assessments. Implications/Conclusions Results suggest a single 0.5-mg/kg dose of esketamine may benefit individuals with PMDD, and the symptom reduction may be comparable with esketamine's effects for MDD. Furthermore, esketamine may induce an antidepressant response in those with PMDD without complication of psychotic symptoms. Future research with controlled designs is warranted.
•Ketamine and Esketamine improve cognition in depression.•Ketamine and Esketamine have similar effect on cognition in depression.•Low doses of Ketamine and Esketamine are cognitively safe in ...depression.
The objective of this study is to evaluate cognition in patients using either ketamine or esketamine to treat TRD. We also evaluate if both ketamine and esketamine as one group influence cognition in patients with TRD. Fifty-four patients with TRD were infused with either ketamine or esketamine and were assessed at three time points: baseline, 24 h, and 7 days after infusion. We applied neuropsychological tests to evaluate executive functions, processing speed, short term memory, and auditory-verbal episodic memory. There is no cognitive difference between ketamine and esketamine, with the exception of one variable. When considered as one group, ketamine and esketamine do not impair cognition; on the contrary, they improve some neuropsychological functions such as visuospatial short-term memory, executive functions, processing speed, and several measures related to episodic verbal memory. Ketamine and esketamine do not present differing cognitive effects when used in antidepressant doses to treat TRD. Furthermore, they rapidly improve many cognitive aspects of patients with TRD at 24 h after the infusion and maintain these effects for at least 7 days.
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