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Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses
Abstract
To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N-methyl-D-aspartate subtype of excitatory amino acid receptor.
Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured.
Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4-hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure.
These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
... These drugs act as noncompetitive antagonists at the PCP binding site of the NMDAR, preventing the influx of calcium ions and reducing the synaptic transmission mediated by glutamate. The psychotomimetic effects of these drugs are dose-dependent and correlate with the degree of NMDAR blockade [88]. ...
NMDA receptors (NMDARs) are a subtype of ionotropic glutamate receptors that mediate excitatory neurotransmission and synaptic plasticity in the brain. NMDARs play important roles in various normal brain functions such as learning, memory, and cognition, but also contribute to the pathogenesis of several developmental, neurological, and psychiatric disorders. Alterations in NMDARs can result in either hypo- or hyperfunction of NMDARs, which can impair neuronal viability, synaptic efficacy, and network oscillations. In this review, we summarize the current knowledge on the involvement of NMDA receptors in Alzheimer’s disease, autism spectrum disorder, epilepsy, and schizophrenia. We also highlight the potential therapeutic strategies that target NMDAR modulation and dysfunction in these disorders.
... However, the conflicting literature on ketamine-induced dissociation raises the question of whether it plays a mediating or necessary role in the anti-depressant response. Indeed, other researchers argue against the potential benefits of ketamine's dissociative effects (Krystal et al., 1994;Berman et al., 2000). ...
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
Background and Hypothesis
The glymphatic system (GS), a brain waste clearance pathway, is disrupted in various neurodegenerative and vascular diseases. As schizophrenia shares clinical characteristics with these conditions, we hypothesized GS disruptions in patients with schizophrenia spectrum disorder (SCZ-SD), reflected in increased brain macromolecule (MM) and decreased diffusion-tensor-image-analysis along the perivascular space (DTI-ALPS) index.
Study Design
Forty-seven healthy controls (HCs) and 103 patients with SCZ-SD were studied. Data included 135 proton magnetic resonance spectroscopy (1H-MRS) sets, 96 DTI sets, with 79 participants contributing both. MM levels were quantified in the dorsal-anterior cingulate cortex (dACC), dorsolateral prefrontal cortex, and dorsal caudate (point resolved spectroscopy, echo-time = 35ms). Diffusivities in the projection and association fibers near the lateral ventricle were measured to calculate DTI-ALPS indices. General linear models were performed, adjusting for age, sex, and smoking. Correlation analyses examined relationships with age, illness duration, and symptoms severity.
Study Results
MM levels were not different between patients and HCs. However, left, right, and bilateral DTI-ALPS indices were lower in patients compared with HCs (P < .001). In HCs, age was positively correlated with dACC MM and negatively correlated with left, right, and bilateral DTI-ALPS indices (P < .001). In patients, illness duration was positively correlated with dACC MM and negatively correlated with the right DTI-ALPS index (P < .05). In the entire population, dACC MM and DTI-ALPS indices showed an inverse correlation (P < .01).
Conclusions
Our results suggest potential disruptions in the GS of patients with SCZ-SD. Improving brain’s waste clearance may offer a potential therapeutic approach for patients with SCZ-SD.
The discovery of rapid-acting antidepressant, ketamine has opened a pathway to a new generation of treatments for depression, and inspired neuroscientific investigation based on a new perspective that non-adaptive changes in the intrinsic excitatory and inhibitory circuitry might underlie the pathophysiology of depression. Nevertheless, it still remains largely unknown how the hypothesized molecular and synaptic levels of changes in the circuitry might mediate behavioral and neuropsychological changes underlying depression, and how ketamine might restore adaptive behavior. Here, we used computational models to analyze behavioral changes induced by therapeutic doses of ketamine, while rhesus macaques were iteratively making decisions based on gains and losses of tokens. When administered intramuscularly or intranasally, ketamine reduced the aversiveness of undesirable outcomes such as losses of tokens without significantly affecting the evaluation of gains, behavioral perseveration, motivation, and other cognitive aspects of learning such as temporal credit assignment and time scales of choice and outcome memory. Ketamine’s potentially antidepressant effect was separable from other side effects such as fixation errors, which unlike outcome evaluation, was readily countered with strong motivation to avoid errors. We discuss how the acute effect of ketamine to reduce the initial impact of negative events could potentially mediate longer-term antidepressant effects through mitigating the cumulative effect of those events produced by slowly decaying memory, and how the disruption-resistant affective memory might pose challenges in treating depression. Our study also invites future investigations on ketamine’s antidepressant action over diverse mood states and with affective events exerting their impacts at diverse time scales.
Background
Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects.
Methods
We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets.
Results
We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level.
Conclusions
These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry.
Funding
This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1–190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016–0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 – 2056) (FXV).
Clinical trial number
NCT03842800
Excitatory amino acid transporters (EAATs) are essential CNS proteins that regulate glutamate levels. Excess glutamate release and alteration in EAAT expression are associated with several CNS disorders. Previously, we identified positive allosteric modulators (PAM) of EAAT2, the main CNS transporter, and have demonstrated their neuroprotective properties in vitro. Herein, we report on the structure–activity relationships (SAR) for the analogs identified from virtual screening and from our medicinal chemistry campaign. This work identified several selective EAAT2 positive allosteric modulators (PAMs) such as compounds 4 (DA-023) and 40 (NA-014) from a library of analogs inspired by GT949, an early generation compound. This series also provides nonselective EAAT PAMs, EAAT inhibitors, and inactive compounds that may be useful for elucidating the mechanism of EAAT allosteric modulation.
Administered a battery of psychological tests (Comrey Personality Scales, State-Trait Anxiety Inventory, Mood Questionnaire, and Health Status Inventory) to 107 female adults 3 hrs prior to surgery under ketamine anesthesia. Results show that moods were more highly related to the psychotropic effects of ketamine than any of the other measures. Some form of counseling intervention that would better prepare patients to cope with the surgical situation might be effective in reducing this emotionality.
Factor analysis of the Bell Reality Testing Inventory items produced three subscales interpreted as dimensions of the reality testing ego function. Replication factor analysis confirmed the factor structure. Subscales were assessed for internal consistency and for age, gender, and social desirability biases. Two subscales, Reality Distortion and Uncertainty of Perception, had low correlations with most Brief Psychiatric Rating Scale (BPRS) symptom scales. The third, Hallucinations and Delusions, correlated significantly with the Hallucinatory Behavior and Unusual Thought Content scales of the BPRS and with BPRS sum scores and Global Assessment Scale scores. Seven criterion groups are compared for percentage of high-scoring subjects and subscale mean values. Schizophrenics, schizoaffectives, and borderlines were most pathological on Reality Distortion and on Hallucinations and Delusions. Borderlines were highest on Uncertainty of Perception. Discriminant analysis differentiated inpatient schizophrenics from inpatients with major affective disorders with 92% classification accuracy. Subscales appear sensitive to variations in psychopathology and may further investigations involving reality testing ego functioning.
A double-blind controlled trial based on 140 women undergoing abortus provocatus was employed to study whether the frequency of side effects after administration of the anaesthetic Ketalar (ketamine) could be reduced by a con-current dose of Rohypnol (flunitrazepam). The control group was given ketamine alone. The dosage of ketamine was 2 mg/kg body weight, supplemented if necessary by 1 mg/kg, in combination with either 2 mg flunitrazepam or placebo. No other anaesthetics were used. On several counts, the combination of ketamine and flunitrazepam was proved to reduce the adverse reactions seen with ketamine alone. Motor restlessness and confusion in the awakening state occurred with significantly less severity and frequency. Amnesia for dreams was significantly more frequent. Memory of dreams was often unpleasant after ketamine alone. The influence on pulse rate was significantly smaller and no significant changes in systolic blood pressure were seen, whereas a significant increase occurred with ketamine alone. Less pronounced fluctuations in diastolic blood pressure occurred with the combination ketamine-flunitrazepam. Respiratory rate increased significantly with both treatments, but respiratory minute volume was lower with the ketamine-flunitrazepam combination.
PIP
A double-blind comparison of ketamine (Ketalar) and ketamine with flunitrazepam (Rohypnol) for anesthesia in 136 abortions was conducted to see whether the combination would reduce the psychomimetic side effects of ketamine. Doses were ketamine 2 mg/kg body weight iv, mixed with 2 mg flunitrazepam or a placebo, and 1 mg/kg ketamine repeated if needed. The side effects significantly reduced were: motor restlessness, confusion requiring sedatives, dreams and nightmares, systolic and diastolic hypertension, tachycardia, and increase in respiratory rate and in respiratory minute volume. Those given ketamine alone required significantly more repeat injections.
Mice were either pretreated with naloxone (10 mg/kg i.p.) and then injected with a hypnotic, or given a similar dose of naloxone simultaneously with a hypnotic (combination treatment). Neither the naloxone pretreatment nor the combination treatment changed the time of on-set or the sleeping duration of urethane, chloral hydrate or ketamine. However, the naloxone pretreatment markedly decreased the on-set time and prolonged the sleeping duration of phenobarbitone and barbitone; naloxone in combination prolonged the sleeping duration of pentobarbitone, phenobarbitone and barbitone.
Mean plasma free-norepinephrine concentration rose significantly (p less than 0.001) during induction of anesthesia with intravenous ketamine (2.0 mg/kg) in 12 patients. In contrast, no change occurred during induction with thiamylal (5.0 mg/kg) in a control group of 8 patients. No significant rise in plasma free-epinephrine concentration occurred in either ketamine or thiamylal groups. These data support the suggestion that increased venous return mediated by the sympathetic nervous system may be responsible for the increased cardiac output and hypertension known to occur during ketamine anesthesia.