Racemic Ketamine Research Articles

Molecular signature underlying (R)-ketamine rapid antidepressant response on anhedonic-like behavior induced by sustained exposure to stress

Anhedonia induced by sustained stress exposure is a hallmark symptom of major depressive disorder (MDD) and in rodents, it can be accessed through the sucrose preference test (SPT). (R)-ketamine is a fast-acting antidepressant with less detrimental side effects and abuse liability compared to racemic ketamine. The present study combined high-throughput proteomics and network analysis to identify molecular mechanisms involved in chronic variable stress (CVS)-induced anhedonia and promising targets underlying (R)-ketamine rapid antidepressant response. Male Wistar rats were subjected to CVS for five weeks. Based on the SPT, animals were clustered into resilient or anhedonic-like (ANH) groups. ANH rats received a single dose of saline or (R)-ketamine (20 mg/kg, i.p.), which was proceeded by treatment response evaluation. After prefrontal cortex collection, proteomic analysis was performed to uncover the differentially expressed proteins (DEPs) related to both anhedonic-like behavior and pharmacological response. The behavioral assessment showed that the ANH animals had a significant decrease in SPT, and that (R)-ketamine responders showed a reversal of anhedonic-like behavior. On a molecular level, anhedonia-like behavior was associated with the downregulation of Neuronal Pentraxin Receptor (Nptxr) and Galectin−1 (Gal-1). These data reinforce a disruption in the inflammatory response, neurotransmitter receptor activity, and glutamatergic synapses in chronic stress-induced anhedonia. (R)-ketamine response-associated DEPs included novel potential targets involved in the modulation of oxidative stress, energetic metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length, converging to biological themes extensively documented in MDD physiopathology. Our data provide valuable insights into the molecular mechanisms underlying the response to (R)-ketamine and highlight these pathways as potential therapeutic targets for anhedonia. By addressing proteins involved in oxidative stress, energy metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length, we can target multiple key factors involved in the pathophysiology of MDD. Modulating these proteins could open avenues for novel therapeutic strategies and deepen our understanding of anhedonia, offering hope for improved outcomes in individuals facing this challenging condition. However, additional studies will be essential to validate these findings and further explore their therapeutic implications.

Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors.

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, δ, and κ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ∼100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system. SIGNIFICANCE STATEMENT: This study found that ketamine and its major biologically active metabolites function as potent allosteric modulators of μ, δ, and κ opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides, such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug.

Morphological correlates of anxiety-related experiences during a ketamine infusion

Objectives: Ketamine exerts rapid antidepressant effects by enhancing neuroplasticity, particularly in the amygdala and hippocampus—regions involved in fear processing and learning. While the role of ketamine’s dissociative effects in its antidepressant response is debated, anxiety experienced during infusion has been negatively correlated with treatment outcomes. Methods: In this single-blind, placebo-controlled study, a subset of 17 healthy volunteers (6 males, 23.12 ± 1.9 years) received intravenously a placebo in the first and 0.5 mg/kg racemic ketamine in the second session. Anxiety-related experiences were assessed by the 5D-ASC score obtained post-infusion, structural magnetic resonance imaging scans were acquired 4 h post-infusion. An anxiety-score was obtained from the 5D-ASC. Relation between post-placebo amygdala volume, hippocampal volume, and its subfields with the anxiety-score were assessed using linear regression models. Results: Results showed a statistically significant negative relation between hippocampal head volume and the anxiety score (β = −0.733, p = 0.006), with trending negative association for each subfield’s head and the score. Conclusion: These findings suggest that anxiety-related experiences during ketamine infusion may be mediated by the hippocampus, with smaller hippocampal volumes leading to more anxiety-related experiences. Thus, hippocampal subfield volumes may be used as a predictor for anxiety-related events during ketamine use and might predict treatment outcome in future approaches.

Efficacy of racemic ketamine or esketamine monotherapy for reducing suicidal ideation in uni- or bipolar depression: a systematic review and meta-analysis.

The current systematic review and meta-analysis examined the effect of racemic ketamine or esketamine on suicidal ideation in individuals with uni- or bipolar depression. We searched the MEDLINE, Embase, Central, PsycINFO, and Web of Science databases to identify randomized controlled trials that examined the effect of racemic ketamine or esketamine monotherapy on suicidal ideation (SI) in individuals with uni- or bipolar depression. The two monotherapies were compared; the primary outcome was the rate of remission of SI, and the secondary outcome was the SI score. The risk ratio was used as an effect size measure for binary variables, while the standardized mean difference was used as an effect size measure for continuous variables. Our meta-analysis included 13 randomized controlled trials involving 1,1109 individuals with uni- or bipolar depression. Patients receiving racemic ketamine monotherapy had a significantly higher acute SI remission rate than those receiving placebo or midazolam (RR = 2.06, 95% CI 1.47 to 2.91, P < 0.0001). Racemic ketamine also led to significantly lower SI scores than placebo or midazolam (SMD = -0.36, 95% CI -0.71 to -0.01, P = 0.04). The evidence for the treatment of SI with esketamine was inconsistent. The pooled effect sizes for long-term anti-SI effects did not reveal significant differences between therapies. Our study indicated the efficacy of racemic ketamine monotherapy for rapidly and transiently reducing SI in individuals with uni- or bipolar depression, but the efficacy of racemic ketamine monotherapy against long-term suicidal ideation remains unclear. There is not -sufficient evidence to support the anti-suicidal effects of esketamine monotherapy.Protocol registration: Prospero registration number: CRD42023434380.

High-order brain interactions in ketamine during rest and task: a double-blinded cross-over design using portable EEG on male participants

Ketamine is a dissociative anesthetic that induces a shift in global consciousness states and related brain dynamics. Portable low-density EEG systems could be used to monitor these effects. However, previous evidence is almost null and lacks adequate methods to address global dynamics with a small number of electrodes. This study delves into brain high-order interactions (HOI) to explore the effects of ketamine using portable EEG. In a double-blinded cross-over design, 30 male adults (mean age = 25.57, SD = 3.74) were administered racemic ketamine and compared against saline infusion as a control. Both task-driven (auditory oddball paradigm) and resting-state EEG were recorded. HOI were computed using advanced multivariate information theory tools, allowing us to quantify nonlinear statistical dependencies between all possible electrode combinations. Ketamine induced an increase in redundancy in brain dynamics (copies of the same information that can be retrieved from 3 or more electrodes), most significantly in the alpha frequency band. Redundancy was more evident during resting state, associated with a shift in conscious states towards more dissociative tendencies. Furthermore, in the task-driven context (auditory oddball), the impact of ketamine on redundancy was more significant for predictable (standard stimuli) compared to deviant ones. Finally, associations were observed between ketamine’s HOI and experiences of derealization. Ketamine appears to increase redundancy and HOI across psychometric measures, suggesting these effects are correlated with alterations in consciousness towards dissociation. In comparisons with event-related potential (ERP) or standard functional connectivity metrics, HOI represent an innovative method to combine all signal spatial interactions obtained from low-density dry EEG in drug interventions, as it is the only approach that exploits all possible combinations between electrodes. This research emphasizes the potential of complexity measures coupled with portable EEG devices in monitoring shifts in consciousness, especially when paired with low-density configurations, paving the way for better understanding and monitoring of pharmacological-induced changes.

Esketamine in depression: putative biomarkers from clinical research.

The discovery of racemic (R, S)-ketamine as a rapid-acting antidepressant and the subsequent FDA approval of its (S)-enantiomer, esketamine, for treatment-resistant depression (TRD) are significant advances in the development of novel neuropsychiatric therapeutics. Esketamine is now recognized as a powerful tool for addressing persistent symptoms of TRD compared to traditional oral antidepressants. However, research on biomarkers associated with antidepressant response to esketamine has remained sparse and, to date, has been largely extrapolated from racemic ketamine studies. Genetic, proteomic, and metabolomic profiles suggest that inflammation and mitochondrial function may play a role in esketamine's antidepressant effects, though these preliminary results require verification. In addition, neuroimaging research has consistently implicated the prefrontal cortex, striatum, and anterior cingulate cortex in esketamine's effects. Esketamine also shows promise in perioperative settings for reducing depression and anxiety, and these effects appear to correlate with increased peripheral biomarkers such as brain-derived neurotrophic factor and serotonin. Further indications are likely to be identified with the continued repurposing of racemic ketamine, providing further opportunity for biomarker study and mechanistic understanding of therapeutic effects. Novel methodologies and well-designed biomarker-focused clinical research trials are needed to more clearly elucidate esketamine's therapeutic actions as well as biologically identify those most likely to benefit from this agent, allowing for the improved personalization of antidepressant treatment.

Nitric Oxide Donor Sodium Nitroprusside Reduces Racemic Ketamine-But Not Esketamine-Induced Pain Relief.

The anesthetic, analgesic and antidepressant drug ketamine produces dissociation with symptoms of psychosis and anxiety, an effect attributed to neuronal nitric oxide depletion following N-methyl-d-aspartate blockade. There is evidence that dissociation induced by racemic ketamine, containing both ketamine enantiomers (S- and R-ketamine) but not esketamine (the S-isomer) is inhibited by nitric oxide (NO) donor sodium nitroprusside (SNP). We tested whether a similar intervention would reduce racemic and esketamine-induced analgesia in a randomized double-blind placebo-controlled trial. Seventeen healthy volunteers were treated with 0.5 μg.kg-1.min-1 SNP or placebo during a 3-h infusion of escalating doses of racemic ketamine (total dose 140 mg) or esketamine (70 mg). Pain pressure threshold (PPT) and arterial blood samples for measurement of S- and R-ketamine and their metabolites, S- and R-norketamine, were obtained. The data were analyzed with a population pharmacokinetic-pharmacodynamic model that incorporated the measured S- and R- ketamine and S- and R-norketamine isomers as input and PPT as output to the model. The potency of the 2 formulations in increasing PPT from baseline by 100% was 0.47 ± 0.12 (median ± standard error of the estimate) nmol/mL for esketamine and 0.62 ± 0.19 nmol/mL for racemic ketamine, reflecting the 52 ± 27% lower analgesic potency of R-ketamine versus S-ketamine. Modeling showed that SNP had no effect on S-ketamine potency but abolished the R-ketamine analgesic effect. Similar observations were made for S- and R-norketamine. Since SNP had no effect on S-ketamine analgesia, we conclude that SNP interacts on R-ketamine nociceptive pathways, possibly similar to its effects on R-ketamine activated dissociation pathways.

Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial

Ketamine has rapid-onset antidepressant activity in patients with treatment-resistant major depression (TRD). The safety and tolerability of racemic ketamine may be improved if given orally, as an extended-release tablet (R-107), compared with other routes of administration. In this phase 2 multicenter clinical trial, male and female adult patients with TRD and Montgomery–Asberg Depression Rating Scale (MADRS) scores ≥20 received open-label R-107 tablets 120 mg per day for 5 days and were assessed on day 8 (enrichment phase). On day 8, responders (MADRS scores ≤12 and reduction ≥50%) were randomized on a 1:1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120 or 180 mg, or placebo, twice weekly for a further 12 weeks. Nonresponders on day 8 exited the study. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13 weeks, starting with the 180 mg dose, using a fixed sequence step-down closed test procedure. Between May 2019 and August 2021, 329 individuals were screened for eligibility, 231 entered the open-label enrichment phase (days 1–8) and 168 responders were randomized to double-blind treatment. The primary objective was met; the least square mean difference of MADRS score for the 180 mg tablet group and placebo was −6.1 (95% confidence interval 1.0 to 11.16, P = 0.019) at 13 weeks. Relapse rates during double-blind treatment showed a dose response from 70.6% for placebo to 42.9% for 180 mg. Tolerability was excellent, with no changes in blood pressure, minimal reports of sedation and minimal dissociation. The most common adverse events were headache, dizziness and anxiety. During the randomized phase of the study, most patient dosing occurred at home. R-107 tablets were effective, safe and well tolerated in a patient population with TRD, enriched for initial response to R-107 tablets. ClinicalTrials.gov registration: ACTRN12618001042235.

248. Cognitive Outcomes Following a Course of Racemic Ketamine: Results From the Randomised, Active-Controlled Ketamine for Adult Depression Study (KADS)

248. Cognitive Outcomes Following a Course of Racemic Ketamine: Results From the Randomised, Active-Controlled Ketamine for Adult Depression Study (KADS)

The effect of prophylactic esketamine in labor and cesarian delivery on the prevention of postpartum depression (PPD): A systematic review and meta-analysis of randomized controlled trials

IntroductionPostpartum depression (PPD) is a common psychiatric illness affecting maternal health, which can lead to poor outcomes for the infant, mother and family. Since the usual pharmacological treatment has low efficacy and a delayed onset of action, new treatment options should be explored. A recent meta-analysis demonstrated positive effects of racemic ketamine on PPD, but limited evidence is available on its more potent derivative esketamine.ObjectivesTo determine the effect of esketamine administered prophylactically during labor on the risk of incidence of PPD at 1 week and 6 weeks after delivery.MethodsPubMed, Scopus and GoogleScholar databases were searched for randomized controlled trials that studied the efficacy of esketamine that screened for PPD using the Edinburgh Postpartum Depression Scale (EPDS). Risk ratio was used to determine the effect of incidence on PPD. Heterogeneity was examined with I2 statistics. A random-effects model was used, as per moderate heterogeneity (I2=59%, p-value&lt;0.05).ResultsWe included 7 RCTs with 1287 patients, 635 having received esketamine (49.3%). Patient-controlled intravenous analgesia (PCIA) or single intravenous dose during the delivery or cesarian section were the main drug delivery methods. Follow-up ranged from 4 weeks to 6 months, and EPDS cut-off scores for depression risk differed between studies, from 9 to 13 points. Dosages varied from 0.2mg/kg to 0.5mg/kg for single-dose administration and 0.1mg/kg to 1.25mg/kg for PCIA. Incidence of PPD at one week (RR: 0.459 95%CI 0.217-0.970; p&lt;0.05; figure 1A) and at 6 weeks (RR: 0.470 95%CI 0.273-0.810; p&lt;0.01; figure 1B) was significantly less common in patients who received esketamine during or after labor. Risk of bias was low in 5 studies and moderate in 2 studies. Risk of publication bias is significant.Image:ConclusionsProphylactic esketamine seems to improve EPDS scores in women at one and six weeks after birth. A more thorough analysis of the adverse effects on maternal and neonatal health are required, and long-term benefits are not fully understood. Larger multicenter studies would be a welcome addition to the issue at hand.Disclosure of InterestNone Declared

Effects of New Psychoactive Substance Esketamine on Behaviors and Transcription of Genes in Dopamine and GABA Pathways in Zebrafish Larvae.

Esketamine (ESK) is the S-enantiomer of ketamine racemate (a new psychoactive substance) that can result in illusions, and alter hearing, vision, and proprioception in human and mouse. Up to now, the neurotoxicity caused by ESK at environmental level in fish is still unclear. This work studied the effects of ESK on behaviors and transcriptions of genes in dopamine and GABA pathways in zebrafish larvae at ranging from 12.4 ng L- 1 to 11141.1 ng L- 1 for 7 days post fertilization (dpf). The results showed that ESK at 12.4 ng L- 1 significantly reduced the touch response of the larvae at 48 hpf. ESK at 12.4 ng L- 1 also reduced the time and distance of larvae swimming at the outer zone during light period, which implied that ESK might potentially decrease the anxiety level of larvae. In addition, ESK increased the transcription of th, ddc, drd1a, drd3 and drd4a in dopamine pathway. Similarly, ESK raised the transcription of slc6a1b, slc6a13 and slc12a2 in GABA pathway. This study suggested that ESK could affect the heart rate and behaviors accompanying with transcriptional alterations of genes in DA and GABA pathways at early-staged zebrafish, which resulted in neurotoxicity in zebrafish larvae.

Stereoselective Pharmacokinetics of Ketamine Administered at a Low Dose in Awake Dogs.

The present study aimed to examine the stereoselective pharmacokinetics of racemic ketamine in dogs at low doses. The secondary aims were to identify associated behavioural effects and propose a ketamine infusion rate. The study was conducted on nine intact male beagles, with each dog undergoing two treatments (BOL and INF). For treatment BOL, an intravenous bolus of 1 mg/kg was administered over 2 min. The treatment INF involved an initial bolus of 0.5 mg/kg given over 1 min, followed by an infusion at 0.01 mg/kg/min for 1 h. Blood samples were collected for pharmacokinetic analysis. The median R/S enantiomer ratio of ketamine remained close to 1 throughout the study. Levels of S-norketamine were significantly higher than those of R-norketamine across all time points. Based on the collected data, the infusion rate predicted to achieve a steady-state racemic ketamine plasma concentration of 150 ng/mL was 0.028 mg/kg/min. Higher scores for behavioural effects were observed within the first five minutes following bolus administration. The most common behaviours observed were disorientation, head movements and staring eyes. Furthermore, employing ROC curve analysis, a racemic ketamine plasma concentration of 102 ng/mL was defined as the cut-off value, correlating with the occurrence of undesirable behavioural patterns.

Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis

ObjectiveIntravenous (IV) racemic ketamine and intranasal (IN) esketamine have demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). This systematic review aims to evaluate the efficacy and safety of ketamine and esketamine at various dosages for depression. MethodsWe included randomized controlled trials (RCTs) with parallel group dose comparison of ketamine and esketamine for depression/TRD. Ovid Medline, Embase, PsycINFO, Scopus and Cochrane databases were searched. Standardized mean differences were calculated using Hedges'-g to complete random effects meta-analysis. The efficacy outcomes were changes in depression outcomes for IV ketamine and IN esketamine respectively. Safety was assessed by reported adverse effects. ResultsA random effects meta-analysis of studies (n = 12) showed efficacy in reducing depression symptoms with IV ketamine (Hedges'g = 1.52 [0.98–2.22], Z = 4.23, p < 0.001) and IN esketamine (Hedges' g = 0.31 [0.18–0.44], Z = 4.53, P < 0.001) compared to control/placebo. Treatment response was observed at IV ketamine doses ≤0.2 mg/kg, >0.2–0.5 mg/kg and > 0.5 mg/kg. Higher IV ketamine doses (>0.5 mg/kg) did not lead to greater treatment response. Esketamine doses of 56–84 mg were superior to 28 mg dose. LimitationsOverall quality of evidence was low and limited by small number of studies. Publication bias was high. ConclusionsThis meta-analysis suggests that IV ketamine may be efficacious at doses as low as 0.2 mg/kg, with increasing dose response at 0.5 mg/kg, without demonstrable increased benefit at 1 mg/kg, based on a small number of studies. Efficacy for IN esketamine increases with doses above 28 mg with best response being found between 56 and 84 mg for reducing depressive symptoms.

Predicting non-response to ketamine for depression: An exploratory symptom-level analysis of real-world data among military veterans

Ketamine helps some patients with treatment resistant depression (TRD), but reliable methods for predicting which patients will, or will not, respond to treatment are lacking. Herein, we aim to inform prediction models of non-response to ketamine/esketamine in adults with TRD. This is a retrospective analysis of PHQ-9 item response data from 120 patients with TRD who received repeated doses of intravenous racemic ketamine or intranasal eskatamine in a real-world clinic. Regression models were fit to patients’ symptom trajectories, showing that all symptoms improved on average, but depressed mood improved relatively faster than low energy. Principal component analysis revealed a first principal component (PC) representing overall treatment response, and a second PC that reflects variance across affective versus somatic symptom subdomains. We then trained logistic regression classifiers to predict overall response (improvement on PC1) better than chance using patients’ baseline symptoms alone. Finally, by parametrically adjusting the classifier decision thresholds, we identified optimal models for predicting non-response with a negative predictive value of over 96 %, while retaining a specificity of 22 %. Thus, we could identify 22 % of patients who would not respond based purely on their baseline symptoms. This approach could inform rational treatment recommendations to avoid additional treatment failures.

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.

Behavioral sensitization and tolerance induced by repeated treatment with ketamine enantiomers in male Wistar rats.

Ketamine has gained significant attention as a fast-acting antidepressant. However, ketamine is also associated with undesirable side effects. In our preclinical study, we explored the behavioral effects of ketamine enantiomers at subanesthetic doses. During repeated intermittent treatment, we examined locomotor stimulation and sensitization, ataxia, and expression of natural behaviors (grooming and rearing). Male Wistar rats were subcutaneously treated repeatedly with either 5 mg/kg of R-ketamine or S-ketamine, 15 mg/kg of R-ketamine, S-ketamine or racemic ketamine, 30 mg/kg of racemic ketamine or saline every third day for three weeks (seven treatments overall). After the first treatment, only 15 mg/kg of S-ketamine induced locomotor stimulation, and both 15 mg/kg of S-ketamine and 30 mg/kg of racemic ketamine induced ataxia. Upon repeated administration, doses of 15 mg/kg of R-ketamine, S-ketamine, and racemic ketamine, as well as 30 mg/kg of racemic ketamine, stimulated locomotion. 15 mg/kg of R-ketamine, S-ketamine, and racemic ketamine additionally resulted in locomotor sensitization. The last administration of 15 mg/kg of S-ketamine, 15 mg/kg of racemic ketamine, and 30 mg/kg of racemic ketamine resulted in ataxia. In the case of 15 mg/kg of S-ketamine, ataxic effects were significantly weaker in comparison to the effects from the first administration, indicating tolerance. Natural behaviors were attenuated after 5 and 15 mg/kg of S-ketamine and 15 and 30 mg/kg of racemic ketamine. Neither of the R-ketamine doses produced such an effect. We conclude that S-ketamine has a stronger behavioral effect than R-ketamine.

How the Food and Drug Administration Drug Approval Process Relates to the Potential Approval of Intravenous Racemic Ketamine for Treatment-resistant Major Depression.

This column focuses on the status of intravenous racemic ketamine for the treatment of patients suffering from a form of major depressive disorder that does not respond to trials of currently available biogenic amine antidepressants. To provide context, the column reviews the 3 pivotal elements of the usual Food and Drug Administration (FDA) drug approval process: (1) the unmet medical need (ie, the indication) for which the drug is being developed, (2) the efficacy of the drug for that condition, and (3) the safety/tolerability of the drug. This column is based on the author's 45-year history of drug development work and is not a statement of the FDA. There are typically 3 phases in the drug development process: (1) studies done in normal volunteers, (2) typically small-scale proof of concept studies, and (3) large-scale registration trials. This third phase is critical in determining the efficacy, safety, and tolerability of the drug in a manner that most closely follows the clinical use of the drug. This column focuses specifically on whether generally small-scale studies done in academic centers are sufficient for drug approval, and it briefly reviews lithium and clozapine as examples of psychiatric medications that had such academic research in the literature, as well as clinical use in other countries. Those data supported the unique value of these medications in patients with bipolar disorder and treatment-resistant schizophrenia (ie, the unmet medical need), respectively, and the findings led American psychiatrists to advocate for FDA approval of these medications. Their efforts led to the needed registration trials for FDA approval of these medications. This column reviews the key features of registration trials and the reason that they are critical for FDA approval, and it discusses 2 special considerations related to the intravenous administration of racemic ketamine. First, racemic ketamine is not esketamine but, instead, it contains R-ketamine in addition to S-ketamine (ie, esketamine). The second consideration is that differences between intravenous and intranasal administration may affect the safety of the drug. While safety concerns were specifically addressed in the registration trials for esketamine, comparable research remains to be done for intravenous racemic ketamine. Understanding how the FDA's drug approval process works is important for prescribers, their patients, and the public.

Rapid Improvement of Post-Partum Depression With Subanesthetic Racemic Ketamine.

Rapid Improvement of Post-Partum Depression With Subanesthetic Racemic Ketamine.

Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS)

BackgroundDue to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). MethodsIn this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5–0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. ResultsResults showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LimitationsThe study included two Cohorts with different dosing regimes. ConclusionsThe findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.

Exploring Esketamine's Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review.

The expansive spectrum of major depressive disorder (MDD) continues to pose challenges for psychiatrists to treat effectively. Oral antidepressant (OAD) medications that alter monoamine neurotransmitters,mainly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), have been the mainstay of therapy for decades. Although these drugs have been largely beneficial, a considerable subset of patients do not respond adequately to multiple conventional therapies administered for an appropriate length of time, leading to a diagnosis of treatment-resistant depression (TRD). Ketamine, a non-monoaminergic drug, has long been known for its beneficial effects on TRD when given intravenously (IV). Between 2019 and 2020, an intranasal formulation of the S (+) enantiomer of racemic ketamine, esketamine (ESK), was granted "breakthrough designation" by the FDA and approved for the indicationsof TRD and MDD patients exhibiting acute suicidal intent. The objective of this narrative review was to review the academic literature and collect clinical evidence that may corroborate intranasal ESK's effectiveness for its approved indications while addressing its safety and tolerability profile, adverse effects, andimpact on cognition. An overview ofthe drug'sorigins,pharmacology, and standard treatment regimen are provided. Theoutcomes from double-blinded randomized control trials (DB-RCTs) of ESK are outlinedto demonstrate the efficacy and safety data leading to its FDA approval, along with its long-term post-market safety outcomes. Comparative trials between ESK and ketamine are then evaluated to highlight ESK's consideration as a more practical alternative toketamine in common clinical practice. The authors further discuss currently approved and developing therapies for TRD,propose future research directions, and identify the inherent limitations of the review and further research. To conduct the research required, three digital databases (PubMed, Medline, and ClinicalTrials.gov) were queried to search for key terms, includingketamine, esketamine, treatment-resistant depression, and biomarkers,using automation toolsalong with selective search engine results.After streamlining the results by title and abstract and removing duplicates, a total of 37 results were chosen, of which 18 are clinical trials. A reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score was the primary efficacy endpoint for most of these clinical trials. In conclusion, intranasal ESK, when used as an adjunct to market OADs, shows greater efficacy in treating TRD and MDD with suicidal intent compared to OADs and placebo alone and provides a more suitable alternative to IV ketamine. It is important to note that further research is required to fully understand the novel mechanism of action of ESK, as well as the establishment of a consensus definition of TRD, which may facilitate better detection and treatment protocols. More focused quantitative and qualitative ESK studies are needed, as well as those pertaining to its use in patients with co-existing mental illnesses.