Dissociation Of Effects Research Articles

Highly efficient strategy of lipopolysaccharide (LPS) decontamination from rHBsAg: synergistic effect of enhanced magnetic nanoparticles (MNPs) as an LPS affinity adsorbent (LAA) and surfactant as a dissociation factor

The interaction of lipopolysaccharide with a recombinant protein is a serious bottleneck, particularly in the purification step of bioprocessing. Recombinant hepatitis B surface antigen (rHBsAg), the active ingredient of the hepatitis B vaccine, is probably contaminated by extrinsic LPS like other biopharmaceuticals. This research intends to eliminate LPS from its mixture with rHBsAg efficiently. Immobilized polymyxin B on magnetic nanoparticles (PMB-MNPs) was synthesized and implemented as an enhanced LPS affinity adsorbent (LAA). The 20–80 EU/dose binary samples with and without surfactant were applied to PMB-MNPs. Formerly, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were examined on the samples to qualitatively show the dissociation effect of the surfactant. Considering the high potential interaction of LPS with HBsAg, the dissociation effects of 0.5 and 1.5% Tween 20 on the binary samples were assessed using immunoaffinity chromatography (IAC) as a quantification tool. The dissociation effect of Tween 20 substantially diminished the interaction, leading to a proportional increase of free LPS up to 66%. The synergetic effect of Tween 20 and privileged LAA was highly effective in eliminating more than 80% of LPS with a remarkable LPS clearance factor of 5.8 and a substantial protein recovery rate of 97%.

Psychotic experiences and dissociation in adolescents: Within-person analysis in the Tokyo teen cohort

Although many cross-sectional studies showed that psychotic experiences (PEs) and dissociation were closely related, the longitudinal association between them remains unknown. Therefore, the aim of the current study was to examine the longitudinal association of these two symptoms throughout adolescence, under the hypothesis that these two symptoms are bidirectionally associated.Data were obtained from a population-based cohort, the Tokyo Teen Cohort study (TTC; N = 3171). PEs and dissociation were assessed at 10, 12, 14, and 16 years of age. PEs were assessed using a total score from five-item self-report questionnaires derived from the Diagnostic Interview Schedule for Children (DISC-C). Dissociation was assessed using subscale scores of the Child Behavior Checklist (CBCL) completed by primary caregivers. We examined the longitudinal relationship between PEs and dissociation using the random intercept cross-lagged panel model (RI-CLPM).The within-person component of the RI-CLPM revealed no significant cross-lagged effect of dissociation on PEs at any time point. On the other hand, there was a significant (p < 0.05) association between PEs at age 14 and dissociation at age 16 (β = 0.106, 95 % CI 0.047–0.165). The between-person component revealed a significant time-invariant relationship between the two symptoms (β = 0.324, 95 % CI 0.239–0.410).The longitudinal relationship between PEs and dissociation was limited at the within-person level, whereas the between-person correlation was significant. The only significant longitudinal pathway was from PEs to dissociation, suggesting that PEs may be a predictor of dissociation in mid-adolescence.

Injectable pH- and Ultrasound-Responsive Dual-Crosslinked Dextran/Chitosan/TiO2 Nanocomposite Hydrogels for Antibacterial Applications.

Combining exogenous and endogenous antibacterial mechanisms has been demonstrated to enhance therapeutic efficacy significantly. This study constructs an innovative type of exogenous and endogenous antibacterial nanocomposite hydrogels with injectable dual-crosslinked networks and dual-stimuli responsiveness. The primary network establishes imine bonds between the functionalized dextran featuring norbornenes and aldehydes (NorAld-Dex) and the quaternized chitosan (QCS). The imine bonds provide self-healing, injectability, and pH-responsiveness to the hydrogel network. The secondary network is established by integrating thiolated mesoporous silica-coated titanium dioxide nanoparticles (TiO2@MS-SH) into the hydrogel network via an ultrasound-activated thiol-norbornene reaction with NorAld-Dex. The microstructures and properties of NorAld-Dex/QCS/TiO2@MS-SH hydrogels can be fine-tuned by adjusting the sonication time to increase the amount of thiol-norbornene crosslinks in the network. Effective antibacterial performance of NorAld-Dex/QCS/TiO2@MS-SH hydrogels at low pH has been demonstrated with the synergistic effect of the acid-induced dissociation of the hydrogel network, protonated QCS, and the reactive oxygen species (ROS) generated by TiO2@MS-SH nanoparticles under ultrasound irradiation. In summary, NorAld-Dex/QCS/TiO2@MS-SH nanocomposite hydrogel is an advanced dual stimuli-responsive antibacterial platform with customizable microstructures and properties, offering great potential for biomedical applications.

Distinct Mindfulness States Produce Dissociable Effects on Neural Markers of Emotion Processing: Evidence From the Late Positive Potential

BackgroundMindfulness has long been theorized to benefit emotion regulation, but despite the ubiquity of the claim, there is little empirical evidence demonstrating how mindfulness modulates the neurophysiology of emotion processing. The current study aimed to fill this gap in knowledge by leveraging a novel research approach capable of discretizing mindfulness into distinct states of open monitoring (OM) and focused attention (FA) to distinguish their influence on multimodal subjective and objective measures of emotion processing. MethodsUtilizing a fully within-participant picture viewing state induction protocol (N = 30), we compared the effects of OM and FA, rigorously contrasted against an active control, on the visually evoked late positive potential (LPP), a neural index of motivated attention. Bayesian mixed modeling was used to distinguish OM versus FA effects on the early and late sustained LPP while evaluating the influence of subjective arousal ratings as a within-participant moderator of the state inductions. ResultsWhen negative picture trials were retrospectively rated as more subjectively arousing, the OM induction reduced the late sustained LPP response, whereas the FA induction enhanced the LPP. ConclusionsAcute manipulation of OM and FA states may reduce and enhance motivated attention to aversive stimuli during conditions of high subjective arousal, respectively. Functional distinctions between different mindfulness states on emotion processing may be most dissociable after accounting for within-participant variability in how stimuli are appraised. These results support the future potential of the state induction protocol for parsing the neural affective mechanisms that underlie mindfulness training programs and interventions.

Spike-timing-dependent plasticity induction reveals dissociable supplementary– and premotor–motor pathways to automatic imitation

Humans tend to spontaneously imitate others' behavior, even when detrimental to the task at hand. The action observation network (AON) is consistently recruited during imitative tasks. However, whether automatic imitation is mediated by cortico-cortical projections from AON regions to the primary motor cortex (M1) remains speculative. Similarly, the potentially dissociable role of AON-to-M1 pathways involving the ventral premotor cortex (PMv) or supplementary motor area (SMA) in automatic imitation is unclear. Here, we used cortico-cortical paired associative stimulation (ccPAS) to enhance or hinder effective connectivity in PMv-to-M1 and SMA-to-M1 pathways via Hebbian spike-timing-dependent plasticity (STDP) to test their functional relevance to automatic and voluntary motor imitation. ccPAS affected behavior under competition between task rules and prepotent visuomotor associations underpinning automatic imitation. Critically, we found dissociable effects of manipulating the strength of the two pathways. While strengthening PMv-to-M1 projections enhanced automatic imitation, weakening them hindered it. On the other hand, strengthening SMA-to-M1 projections reduced automatic imitation but also reduced interference from task-irrelevant cues during voluntary imitation. Our study demonstrates that driving Hebbian STDP in AON-to-M1 projections induces opposite effects on automatic imitation that depend on the targeted pathway. Our results provide direct causal evidence of the functional role of PMv-to-M1 projections for automatic imitation, seemingly involved in spontaneously mirroring observed actions and facilitating the tendency to imitate them. Moreover, our findings support the notion that SMA exerts an opposite gating function, controlling M1 to prevent overt motor behavior when inadequate to the context.

(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders.

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.

Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson disease

Depression in Parkinson disease (PD) is common, is disabling and responds poorly to standard antidepressants. Motivational symptoms of depression are particularly prevalent in PD and emerge with loss of dopaminergic innervation of the striatum. Optimizing dopaminergic treatment for PD can improve depressive symptoms. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known. Using data from a large (n = 412) longitudinal study of patients with newly diagnosed PD followed over 5 years, we investigated whether there are dissociable effects of dopaminergic medications on different depression symptom dimensions in PD. Previously validated ‘motivation’ and ‘depression’ dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter imaging. We identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists were shown to be effective for treatment of motivational symptoms of depression. In contrast, monoamine oxidase-B inhibitors improved both depressive and motivation symptoms, albeit the latter effect is attenuated in patients with more severe striatal dopaminergic neurodegeneration.

Clinical signs of nitrous oxide use: case report and review of the literature

Nitrous oxide is used medically as an anesthetic agent; in the food industry as a propellant for condiments; and recreationally for its euphoric and dissociative effects. We report three cases of nitrous oxide misuse causing severe, symptomatic cobalamin (vitamin B12) deficiency in which signs of nitrous oxide use per se, as well as signs of toxicity, were observed, including characteristic palmar calluses over the metacarpal heads, and frostbite. These signs may assist clinicians in the recognition of nitrous oxide use and the timely diagnosis of nitrous oxide toxicity.

Social influences on the relationship between dissociation and psychotic-like experiences.

Shame is experienced as a threat to social self, and so activates threat-protective responses. There is evidence that shame has trauma-like characteristics, suggesting it can be understood within the same conceptual framework as trauma and dissociation. Evidence for causal links among trauma, dissociation, and psychosis thus warrant the investigation of how shame may influence causal mechanisms for psychosis symptoms. This study tested the interaction between dissociation and shame, specifically external shame (feeling shamed by others), in predicting psychotic-like experiences (PLEs) six months later in a general population sample (N = 314). It also tested if social safeness moderates these effects. A longitudinal, online questionnaire design tested a moderation model (dissociation-shame) and a moderated moderation model (adding social safeness), using multiple regressions with bootstrap procedures. Although there was no direct effect of dissociation on PLEs six months later, there was a significant interaction effect with shame, controlling for PLEs at baseline. There were complex patterns in the directions of effects: For high-shame-scorers, higher dissociation predicted higher PLE scores, but for low-shame-scorers, higher dissociation predicted lower PLE scores. Social safeness was found to significantly moderate these interaction effects, which were unexpectedly more pronounced in the context of higher social safeness. The results demonstrate evidence for an interaction between dissociation and shame on its impact on PLEs, which manifests particularly for those experiencing higher social safeness. This suggests a potential role of social mechanisms in both the etiology and treatment of psychosis, which warrants further testing in clinical populations.

The Mediating Role of Affect Dysregulation and Dissociation in the Relationship Between Attachment and Compulsive Online Shopping: A Path Analysis Model.

Online shopping has been described by the scientific literature both for its benefits and the potential risks when excessive usage is involved. Indeed, compulsive online shopping is commonly conceptualized as a potential behavioural addiction that substantially impacts the lives of individuals afflicted by it. In light of this, the present research aimed at exploring the association between possible risk and protective factors for compulsive online shopping, by specifically exploring the role of adult attachment, affect dysregulation, and dissociation. 285 participants (75% females, 25% males; Mage = 31.57, SD = 11.379) were involved in the research and completed an online survey. The collected data was analysed implementing a path analysis model. Results showed significant total effects in the relationship between secure/fearful attachment patterns and compulsive online shopping. Such associations were significantly mediated by the sequential effect of affect dysregulation and dissociation. The present study provides useful information to guide tailored interventions concerning both preventive activity and clinical practice.

First-in-Human Predictions of Hepatic Clearance for Drugs With the Well-Stirred Model: Comparative Assessment Between Models of Fraction Unbound Based Either on the Free Drug Hypothesis, Albumin-Facilitated Hepatic Uptake or Dynamic Binding Kinetics

The well-stirred model (WSM) is commonly used to predict the hepatic clearance in vivo (CLH) of drugs. The necessary intrinsic clearance of the unbound drug (CLint-in vitro-unbound) is generated in the in vitro assays in the presence of microsomes or hepatocytes but in the absence of plasma proteins. The value of CLint-in vitro-unbound can be extrapolated with the fraction unbound determined in vitro in plasma (fup) only if the fraction unbound in vivo in liver is the same. However, this approach resulted to a systematic underprediction bias of CLH. With the goal of reducing this bias, two new models of fraction unbound were published in this journal. These models estimate the binding kinetics of the rates of association and dissociation of the drug-protein complex and propose that more dissociation in the liver compared to plasma will increase the fraction unbound available for the metabolism. Consequently, these two models generated higher values of fraction unbound, implying a lower underprediction bias of CLH with the WSM. The first model was developed by Poulin et al. and is referring to the value of fup that is adjusted (fu-adjusted) to quantify the effect of a full dissociation of the drug-protein complex at the hepatocyte membrane in accordance with the theory of the albumin-facilitated hepatic uptake. A second model was developed by Yan et al. who presented a dynamic fraction unbound (fu-dynamic) measuring the real dissociation kinetics of the drug-protein complex with a new in vitro assay in the presence and absence of a recombinant liver enzyme in plasma. Therefore, the objective of this study was to make the first comparative assessment between these two models. The results indicate that, in general, the WSM combined with the values of fu-adjusted was the most accurate approach for predicting CLH. The WSM combined with the values of fu-dynamic has underperformed particularly with the acidic and neutral drugs binding to the albumin and presenting a low metabolic turnover in vitro. Therefore, the new in vitro assay for fu-dynamic gave an underprediction bias of CLH for these drug properties. However, the values of fu-adjusted are significantly higher than those values of fu-dynamic, and, this resulted to no underprediction bias, which is reinforcing the theory of the ALB-facilitated hepatic uptake. For the other neutral and acidic drugs, the models of fu-dynamic and fu-adjusted are in closer agreement. Finally, for the basic drugs, the models of fu-adjusted and fu-dynamic as well as a third model only considering a pH gradient effect on fup are almost accurately equivalent.

Dissociable effects of hunger, exposure and sensory overlap on flavour liking

The hedonic value of a flavour stimulus is shaped by familiarity with the combination of its sensory components and the perceiver’s metabolic state. While the relationship between these processes has important implications for understanding food acceptance, interactions between them and their potential specificity to the specific sensory features of the food consumed remain to be defined. In two preregistered experiments, we combined a sensory dilution series with a metabolic state modulation to examine whether hunger affected perceived flavour pleasantness across different levels of sensory concordance. Both experiments consisted of two sessions, whereby healthy participants evaluated the pleasantness of olfactory-gustatory stimuli – once while sated from a standardised meal and once while hungry. Experiment I demonstrated that perceived congruence of odour and taste strongly predicted flavour pleasantness, with no significant additive or interactive hunger effects. Experiment II replicated these results with a larger sample and found no sensory specific modulation of pleasantness. Importantly, exploratory analyses on data from Experiment II indicated that hunger effects were partially counteracted by interactions with prior exposure, where pleasantness enhancement through hunger was stronger for initial exposure under sated conditions. Pre-registered confirmatory analyses replicated this effect on the independent dataset from Experiment I. No interactions between sensory concordance and metabolic state were observed. Our findings demonstrate a robust effect of sensory concordance on pleasantness across metabolic states. Additive pleasantness enhancement by hunger is vulnerable to learning by prior exposure. Synergies between these determinants of hedonic value provide novel insights into strategies for dietary change which merit further investigation.

Chemogenetic inactivation of the nucleus reuniens and its projections to the orbital cortex produce deficits on discrete measures of behavioral flexibility in the attentional set-shifting task

The nucleus reuniens (RE) of the ventral midline thalamus is a critical node in the communication between the orbitomedial prefrontal cortex (OFC) and the hippocampus (HF). While RE has been shown to directly participate in memory-associated functions through its connections with the medial prefrontal cortex and HF, less is known regarding the role of RE in executive functioning. Here, we examined the involvement of RE and its projections to the orbital cortex (ORB) in attention and behavioral flexibility in male rats using the attentional set shifting task (AST). Rats expressing the hM4Di DREADD receptor in RE were implanted with indwelling cannulas in either RE or the ventromedial ORB to pharmacologically inhibit RE or its projections to the ORB with intracranial infusions of clozapine-N-oxide hydrochloride (CNO). Chemogenetic-induced suppression of RE resulted in impairments in reversal learning and set-shifting. This supports a vital role for RE in behavioral flexibility – or the ability to adapt behavior to changing reward or rule contingencies. Interestingly, CNO suppression of RE projections to the ventromedial ORB produced impairments in rule abstraction – or dissociable effects elicited with direct RE suppression. In summary, the present findings indicate that RE, mediated in part by actions on the ORB, serves a critical role in the flexible use of rules to drive goal directed behavior. The cognitive deficits of various neurological disorders with impaired communication between the HF and OFC, may be partly attributed to alterations of RE -- as an established intermediary between these cortical structures.

Alterations in food preference and stress reactivity in mice with a knockout of MeCP2 in POMC neurons

Methyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an overweight phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased motivation to obtain food reward or enhancements in food preference. Here, we show that mice deficient in MeCP2 specifically in pro-opiomelanocortin (POMC) neurons have an increased preference for high fat diet but do not have a greater motivation to obtain food reward, relative to wildtype (WT) littermate controls. We also demonstrate that POMC-Cre MeCP2 knockout (KO) mice have increased body weight after long-term high fat diet exposure as well as elevated plasma leptin and corticosterone (CORT) levels compared to wildtype mice. Given that our POMC-Cre MeCP2 KO mice have elevated CORT, we wanted to determine if our KO mice also respond differentially to early life stress such as maternal separation stress compared to WT controls. Collectively, our data suggest that POMC-specific loss-of-function Mecp2 mutations leads to dissociable effects on the rewarding/motivational properties of food as well as changes to hormones associated with body weight homeostasis and stress and could underlie differential behavioral responses to early life stress. NIGMS 1SC1GM144190-01 (ESN), Texas Woman's University internal funds. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Protocol for a randomised controlled trial of ketamine versus ketamine and behavioural activation therapy for adults with treatment-resistant depression in the community

IntroductionAlthough short-term benefits follow parenteral ketamine for treatment-resistant major depressive disorder (TR-MDD), there are challenges that prevent routine use of ketamine by clinicians. These include acute dissociative effects of parenteral...

Working process model development of the gas turbine engine combustor fueling on methanol

The use of methanol as a fuel for aircraft and stationary gas turbine engines (GTE) is a priority direction in engine building. It is well known that when modeling the GTE performances using first-level mathematical models, there is an error in calculating specific fuel consumption, which is caused by the simplified description of the GTE combustor working process. The object of the study is the working process in the GTE combustor fueling on methanol. The peculiarity of the developed mathematical model of the working process of the GTE combustor is the use of enthalpy dependencies on temperature, pressure, and mixture composition. Enthalpy dependencies in this form implicitly account for the effect of thermal dissociation and allow for the correct formulation of the equivalent combustion reaction path. For two components (H2O and CO2), accounting for pressure leads to the fact that at standard temperature and partial pressures exceeding the saturation pressure, these components exist in a liquid state. This situation, with a constant enthalpy increment in the equivalent process of heating the combustion products from the standard temperature to the temperature at the end of adiabatic heat supply, decreases this temperature. Clarification of the temperature at the combustor outlet leads to changes in all calculated combustor performances, including the combustor fuel air ratio. The calculation results of the fuel air ratio are compared with known experimental data of the General Electric CF6-80A engine combustor (USA). The average calculation error of the fuel air ratio does not exceed 4 %. The developed model can be implemented in existing and developing mathematical models of gas turbine engines for temperatures at the end of the combustion process below 2,600 K

Arousal and valence have dissociable effects on responses to schematic emotional faces.

Studies examining behavioural responses to emotional stimuli usually report one of two patterns of responses to negative stimuli. Some studies find faster responses to negative material. Other studies find slower responses to negative stimuli. While the attentional mechanisms proposed to explain these findings (attentional capture in the former case, delayed disengagement in the latter) are not at odds with one another, the behavioural findings do need to be reconciled. We posit that arousal, being the primary differentiator of threatening and nonthreatening stimuli, needs to be more carefully considered. To this end, two experiments were conducted evaluating the role of stimulus arousal and valence in the processing of schematic emotional faces. In Experiment 1, stimulus arousal was manipulated via the presence or absence of eyebrows in the schematic faces in a faces flanker task. Results showed faster responses to faces with eyebrows but no differences in the faces flanker asymmetry between faces with and without eyebrows. In Experiment 2, participants rated the faces on an evaluative space grid. Results showed the presence of the eyebrows had a greater impact on negative ratings for negative faces than for the other expressions. This suggests that stimulus valence and arousal were manipulated by the eyebrows and the reaction time differences could not be attributed purely to perceptual differences. Together these results suggests that both valence and arousal impact the processing of emotional schematic faces, and that these effects are dissociable. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exploring the multifaceted potential of (R)-ketamine beyond antidepressant applications.

(R, S)- and (S)-ketamine have made significant progress in the treatment of treatment-resistant depression (TRD) and have become a research focus in recent years. However, they both have risks of psychomimetic effects, dissociative effects, and abuse liability, which limit their clinical use. Recent preclinical and clinical studies have shown that (R)-ketamine has a more efficient and lasting antidepressant effect with fewer side effects compared to (R, S)- and (S)-ketamine. However, a recent small-sample randomized controlled trial found that although (R)-ketamine has a lower incidence of adverse reactions in adult TRD treatment, its antidepressant efficacy is not superior to the placebo group, indicating its antidepressant advantage still needs further verification and clarification. Moreover, an increasing body of research suggests that (R)-ketamine might also have significant applications in the prevention and treatment of medical fields or diseases such as cognitive disorders, perioperative anesthesia, ischemic stroke, Parkinson's disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This article briefly reviews the mechanism of action and research on antidepressants related to (R)-ketamine, fully revealing its application potential and development prospects, and providing some references and assistance for subsequent expanded research.

Experiences of Awe Mediate Ketamine’s Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression

BackgroundKetamine, an NMDA receptor antagonist, provides rapid antidepressant effects. Although much research has focused on neural and molecular mechanisms of action, it is critical to also consider psychological mechanisms that may contribute to its therapeutic efficacy. The construct of an awe-inducing experience, which is a well-validated psychological phenomenon tied to emotional well-being, had not been applied previously in ketamine research. MethodsOne hundred sixteen participants with depression, 77 of whom received a ketamine infusion (0.5 mg/kg over 40 minutes) and 39 patients who received saline placebo, completed a validated measure of awe (the Awe Experience Scale [AWE-S]) at 40 minutes postinfusion. AWE-S scores were examined as potential mediators of depression outcomes (% improvement in Montgomery–Åsberg Depression Rating Scale score) at 5 postinfusion time points (24 hours and 5, 12, 21, and 30 days). Dissociative effects, measured by Clinician-Administered Dissociative States Scale scores, were tested in parallel mediation models for comparison. ResultsWe found that the psychological experience of awe was strongly reported by participants during ketamine infusion, but not saline infusion, and there were significant associations between total AWE-S scores and Montgomery–Åsberg Depression Rating Scale score improvement (% change) in the ketamine arm at all 5 time points. Furthermore, at all 5 time points, total AWE-S scores statistically mediated the relationship between ketamine and Montgomery–Åsberg Depression Rating Scale scores. By contrast, Clinician-Administered Dissociative States Scale scores did not mediate outcomes at any time point. ConclusionsKetamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.

Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.

We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.