Is (R)-ketamine a potential therapeutic agent for treatment-resistant depression with less detrimental side effects? A review of molecular mechanisms underlying ketamine and its enantiomers

Scotton, Ellen; Antqueviezc, Bárbara; Vasconcelos, Mailton; Dalpiaz, Giovana; Géa, Luíza Paul; Goularte, Jéferson Ferraz; Colombo, Rafael; Rosa, Adriane Ribeiro

doi:10.1016/j.bcp.2022.114963

Cited by 18 publications

(13 citation statements)

References 237 publications

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“…( 6) The intermediate variables were brought into the observation equation to calculate the predicted EEG at the timepoint of the experiment. (7) The EEG calculated for each sigma point was multiplied by the corresponding weights and added together. ( 8) By comparing the predicted EEG to the rEEG, we updated the posterior estimate augmentation matrix, Kalman gain and process covariance by the corresponding equation.…”

Section: Model Parameter Estimation Based On Unscented Kalman Filter ...mentioning

confidence: 99%

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Tracking the effects of propofol, sevoflurane and (S)-ketamine anesthesia using an unscented Kalman filter-based neural mass model

et al. 2023

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Objective: Neural mass model (NMM) has been widely used to investigate the neurophysiological mechanisms of anesthestic drugs induced general anesthesia (GA). However, whether the parameters of NMM could track the effects of anesthesia still unknown.Approach: We proposed using the cortical NMM (CNMM) to infer the potential neurophysiological mechanism of three different anesthetic drugs (i.e., propofol, sevoflurane, and (S)-ketamine) induced GA, and we employed unscented Kalman filter (UKF) to track any change in raw electroencephalography (rEEG) in frontal area during GA. We did this by estimating the parameters of population gain [i.e., excitatory/inhibitory postsynaptic potential (EPSP/IPSP, i.e., parameter A/B in CNMM) and the time constant rate of EPSP/IPSP (i.e., parameter a/b in CNMM). We compared the rEEG and simulated EEG (sEEG) from the perspective of spectrum, phase-amplitude coupling (PAC), and permutation entropy (PE). Main results: Under three estimated parameters (i.e., A, B, and a for propofol/sevoflurane or b for (S)-ketamine), the rEEG and sEEG had similar waveforms, time-frequency spectra, and PAC patterns during GA for the three drugs. The PE curves derived from rEEG and sEEG had high correlation coefficients (propofol: 0.97±0.03, sevoflurane: 0.96±0.03, (S)-ketamine: 0.98±0.02) and coefficients of determination (R2) (propofol: 0.86±0.03, sevoflurane: 0.68±0.30, (S)-ketamine: 0.70±0.18). Except for parameter A for sevoflurane, the estimated parameters for each drug in CNMM can differentiate wakefulness and non-wakefulness states. Compared with the simulation of three estimated parameters, the UKF-based CNMM had lower tracking accuracy under the simulation of four estimated parameters (i.e., A, B, a, and b) for three drugs.Significance: The results demonstrate that a combination of CNMM and UKF could track the neural activities during GA. The EPSP/IPSP and their time constant rate can interpert the anesthetic drug’s effect on the brain, and can be used as a new index for depth of anesthesia monitoring.

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Section: Model Parameter Estimation Based On Unscented Kalman Filter ...mentioning

confidence: 99%

“…Ketamine is a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers. Compared with (R)-ketamine, (S)-ketamine has higher affinity for NMDA receptor and higher anesthetic efficacy, and is unlikely to cause psychosis and other adverse reactions [7,8]. Thus, the (S)-ketamine is more popular in clinical application.…”

Section: Introductionmentioning

confidence: 99%

Tracking the effects of propofol, sevoflurane and (S)-ketamine anesthesia using an unscented Kalman filter-based neural mass model

et al. 2023

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“…This directly led to adjustments in how esketamine treatment was offered for this population. This study was conducted on oral esketamine; we currently do not know whether other administration methods or enantiomers have similar or distinct effects; future studies should also investigate whether other approaches are more suitable for such treatments (65). A limitation was that we only interviewed patients who finished their initial six-week treatment.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

Holding on or letting go? Patient experiences of control, context, and care in oral esketamine treatment for treatment-resistant depression: A qualitative study

et al. 2022

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BackgroundKetamine and its enantiomer esketamine represent promising new treatments for treatment-resistant depression (TRD). Esketamine induces acute, transient psychoactive effects. How patients perceive esketamine treatment, and which conditions facilitate optimal outcomes, remains poorly understood. Understanding patient perspectives on these phenomena is important to identify unmet needs, which can be used to improve (es)ketamine treatments.AimsTo explore the perspectives of TRD patients participating in “off label” oral esketamine treatment.Materials and methodsIn-depth interviews were conducted with 17 patients (11 women) after a six-week, twice-weekly esketamine treatment program, and subsequently after six months of at-home use. Interviews explored participants’ perspectives, expectations, and experiences with esketamine treatment. Audio interviews were transcribed verbatim and analysed following an Interpretative Phenomenological Analysis (IPA) framework.ResultsKey themes included overwhelming experiences; inadequate preparation; letting go of control; mood states influencing session experiences; presence and emotional support, and supportive settings. Patients’ attempts to let go and give into vs. attempts to maintain control over occasionally overwhelming experiences was a central theme. Multiple factors influenced patients’ ability to give into the experience and appeared to impact their mood and anxiety about future sessions, including level of preparation and education, physical and emotional support, and setting during the session.ConclusionBetter preparation beforehand, an optimized treatment setting, and emotional and psychological support during (es)ketamine sessions can help patients to “let go” and may lead to better quality of care and outcomes. Recommendations to improve quality of patient care in (es)ketamine treatment are provided, including suggestions for the training of nurses and other support staff.

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“…The Food and Drug Administration (FDA) and European Medicines Agency (EMA) recently approved low‐dose intranasal S‐ket for use in people with treatment‐resistant depression following findings from multiple clinical trials of rapid‐onset, robust anti‐depressant effects (Canuso et al, 2018; Daly et al, 2021; Singh et al, 2016; Turner, 2019). Other studies, however, suggest that R‐ket may have more clinical relevance as it is associated with fewer unwanted psychotomimetic or dissociative symptoms and thus might be better tolerated by patients (Fukumoto et al, 2017; Leal et al, 2021) and several preclinical studies report that R‐ket has longer lasting anti‐depressant effects (Scotton et al, 2022; Yang et al, 2015; Zhang et al, 2014). While multiple rodent studies have shown anxiolytic effects of acute RS‐ket at sub‐anesthetic doses (.1–15 mg/kg) (Camargo et al, 2021; Fraga et al, 2018; Hou et al, 2022), limited studies have investigated the differential effects and behavioral responses induced by the two enantiomers in mice.…”

Section: Introductionmentioning

confidence: 99%

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

Vinnakota,

Schroeder,

et al. 2023

J of Neuroscience Research

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Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis‐like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia‐relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia‐relevant NMDAR antagonist‐induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia‐relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S‐ketamine enantiomer (S‐ket), and the ketamine metabolite R‐norketamine (R‐norket) on locomotor activity, anxiety‐related behavior, and recognition and short‐term spatial memory. GluN2D‐KO mice showed a blunted locomotor response to R‐norket, S‐ket, and PCP, a phenotype present in both sexes. GluN2D‐KO mice of both sexes showed an anxious phenotype and S‐ket, R‐norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S‐ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex‐specific effects of NMDAR antagonists and on the differential effects of the R‐ and S‐ket enantiomers.

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Is (R)-ketamine a potential therapeutic agent for treatment-resistant depression with less detrimental side effects? A review of molecular mechanisms underlying ketamine and its enantiomers

Cited by 18 publications

References 237 publications

Tracking the effects of propofol, sevoflurane and (S)-ketamine anesthesia using an unscented Kalman filter-based neural mass model

Tracking the effects of propofol, sevoflurane and (S)-ketamine anesthesia using an unscented Kalman filter-based neural mass model

Holding on or letting go? Patient experiences of control, context, and care in oral esketamine treatment for treatment-resistant depression: A qualitative study

Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist‐induced behavioral disruptions in male and female mice

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