Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/kg/hr) in 26 ethanol-dependent inpatients who were sober for at least one month prior to testing. This study found that nimodipine reduced the capacity of ketamine to induce psychosis, negative symptoms, altered perception, dysphoria, verbal fluency impairment, and learning deficits. Nimodipine improved memory function, but had no other intrinsic behavioral activity in this patient group. Nimodipine pretreatment attenuated the perceived similarity of ketamine effects to ethanol as well as ketamine-induced euphoria and sedation. However, nimodipine did not reduce the stimulant effects of ketamine. These data suggest that antagonism of L-type VSCCs attenuates the behavioral effects of NMDA antagonists in humans. They support the continued evaluation of nimodipine in the treatment of neuropsychiatric disorders. They also suggest that drugs, such as ethanol, that combine NMDA and L-type VSCC antagonism may have enhanced tolerability without attenuation of their stimulant effects.
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PMID:Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists. 1175 Jan 86

Ketamine, an antagonist N-Methyl-D-Aspartate receptor, induces a broad range of anomalies in healthy subjects similar to those observed in psychosis. Previous studies have shown that information sensorimotor processing was impaired in patients with schizophrenia. The aim of the study was to assess the effects of subanesthetic doses of ketamine on behavior symptoms and information processing in healthy volunteers. A double-blind, crossover, placebo-controlled study was performed with eight subjects. Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, and Scale for the Assessment of Positive Symptoms assessed behavior changes. Information processing was assessed using a choice reaction time. Three experimental factors (stimulus intensity, stimulus response compatibility, and foreperiod duration) chosen to affect a different stage of information processing were manipulated. Our study has demonstrated that administration of ketamine produced significant effects on Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, and Scale for the Assessment of Positive Symptoms scores. Results on choice reaction time demonstrated a significant longer reaction time under ketamine. Effects of stimulus intensity and compatibility stimulus response were similar under ketamine and under placebo. Moreover, there was a specific interaction between ketamine and foreperiod. This interaction indicated that foreperiod's effect was more prolonged under ketamine (29 ms) than under placebo (17 ms). These results showed that the clinical effects of ketamine were associated with schizophrenic-like impairments on choice reaction time in healthy subjects.
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PMID:Effects of subanesthetic doses of ketamine on sensorimotor information processing in healthy subjects. 1198 Dec 37

Ketamine and PCP are commonly used as selective NMDA receptor antagonists to model the putative hypoglutamate state of schizophrenia and to test new antipsychotics. Recent findings question the NMDA receptor selectivity of these agents. To examine this further, we measured the affinity of ketamine and PCP for the high-affinity states of the dopamine D(2) and serotonin 5-HT(2) receptor and found that ketamine shows very similar affinity at the NMDA receptor and D(2) sites with a slightly lower affinity for 5-HT(2) (0.5 microM, 0.5 microM and 15 microM respectively), while PCP shows similar affinity for the NMDA and 5-HT(2) sites, with a slightly lower affinity for the D(2) site (2 microM, 5 microM and 37 microM respectively). Further, ketamine and PCP in clinically relevant doses caused a significant increase in the incorporation of [(35)S]GTP-gamma-S binding in CHO-cells expressing D(2) receptors, which was prevented by raclopride, suggesting a partial agonist effect at the D(2) receptor. Thus, ketamine and PCP may not produce a selective hypoglutamate state, but more likely produce a non-selective multi-system neurochemical perturbation via direct and indirect effects. These findings confound the inferences one can draw from the ketamine/PCP models of schizophrenia.
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PMID:NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. 1223 76

Disruption of facial emotion perception occurs in neuropsychiatric disorders where the expression of emotion is dulled or blunted, for example depersonalization disorder and schizophrenia. It has been suggested that, in the clinical context of emotional blunting, there is a shift in the relative contribution of brain regions subserving cognitive and emotional processing. The non-competitive glutamate receptor antagonist ketamine produces such emotional blunting in healthy subjects. Therefore, we hypothesised that in healthy subjects ketamine would elicit neural responses to emotional stimuli which mimicked those reported in depersonalization disorder and schizophrenia. Thus, we predicted that ketamine would produce reduced activity in limbic and visual brain regions involved in emotion processing, and increased activity in dorsal regions of the prefrontal cortex and cingulate gyrus, both associated with cognitive processing and, putatively, with emotion regulation. Measuring BOLD signal change in fMRI, we examined the neural correlates of ketamine-induced emotional blunting in eight young right-handed healthy men receiving an infusion of ketamine or saline placebo while viewing alternating 30 s blocks of faces displaying fear versus neutral expressions. The normal pattern of neural response occurred in limbic and visual cortex to fearful faces during the placebo infusion. Ketamine abolished this: significant BOLD signal change was demonstrated only in left visual cortex. However, with ketamine, neural responses were demonstrated to neutral expressions in visual cortex, cerebellum and left posterior cingulate gyrus. Emotional blunting may be associated with reduced limbic responses to emotional stimuli and a relative increase in the visual cortical response to neutral stimuli.
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PMID:Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study. 1263 89

The N-methyl-D-aspartate (NMDA) antagonist, ketamine, produces neurobehavioural symptoms that mimic aspects of schizophrenia. Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is decreased in chronically ill, medicated schizophrenic patients and in animals treated acutely with NMDA antagonists. We tested the hypothesis that ketamine would produce psychotic symptoms and reduce PPI in healthy humans. Twenty male volunteers received placebo and ketamine in a within-subject, double-blind, cross-over design with 0.23 mg/kg ketamine hydrochloride or saline as a loading dose, followed by 0.5 mg/kg ketamine or saline over 45 min. Prepulse to pulse intervals were 30 ms and 120 ms. The Brief Psychiatric Rating Scale (BPRS) and the Clinician Administered Dissociative States Scale (CADSS) were administered. Ketamine produced a significant increase in PPI and significantly reduced startle magnitude, but did not alter habituation. Ketamine produced significant increases in BPRS and CADSS scores, with symptoms mimicking the negative and disorganisation symptoms of psychosis. In contrast to effects in rodents, this low dose of ketamine produced an increase in PPI despite producing psychopathological symptoms consistent with the NMDA psychosis model. These findings suggest that the cognitive and PPI changes of NMDA antagonists are not consistently linked at a phenomenological or neurochemical level.
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PMID:Low dose ketamine increases prepulse inhibition in healthy men. 1268 71

Schizophrenic patients suffer from positive (delusions, hallucinations) and negative signs (social withdrawal) as well as emotional disturbance that included quantitative (blunted affect) and qualitative impairments (discordance of emotional level). Ketamine, a phencyclidine derivative, is a non competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. In healthy subjects its administration induces some positive symptoms (perceptual distortions.), negative symptoms (emotional deficit, apathy, social withdrawal) and cognitive changes (memory impairments and perseverations) that resemble some aspects of the symptoms of schizophrenia. A double blind cross over, placebo controlled was performed in 12 normal subjects with 2 sessions separated by one week of wash-out to determine ketamine-induced effects on behavioral and emotional responses. During each session, subjects received either ketamine or placebo (saline) infusion. A subanesthetic dose of ketamine (0,5 mg/kg) was administered by constant perfusion over 60 min. Behavioral and cognitive responses were assessed using positive and negative symptoms scales (BPRS, items from SAPS and SANS), vigilance and mood visual analog scale, subjective feelings using the Addiction Research Center Inventory (ARCI) and the Profile of Mood States (POMS). Using Philippot's method, emotions were elicited by films segments which induce a diversity of predictable emotions (fear, anger, sadness, joy, disgust and neutral state) and emotional responses were assessed by the Differential Emotions Scale (DES Izard). Low dose of ketamine induced significant effects on 7-items BPRS score (positive and negative items) and significant effects on positive and negative symptoms from SANS and SAPS. This was associated with emotional blunting of visually-induced responses that resemble aspects of schizophrenic emotional impairments. Ketamine impaired ARCI subscales (benzedrine subscale, pentobarbital-chlorpromazine subscale and LSD subscale). The recent findings of ketamine's pharmacology and imaging studies allow to draw several hypothesis related to neurotransmitter systems (glutamate, dopamine, serotonin interactions) and cerebral areas (particularly prefrontal cortex, anterior cingulate cortex, hippocampus) underlying some of these ketamine-induced effects.
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PMID:[Effects of a subanaesthetic dose of ketamine on emotional and behavioral state in healthy subjects]. 1290 92

N-methyl-D-aspartate (NMDA) receptor antagonists have been demonstrated to induce schizophrenia-like symptoms and cognitive impairment in humans. The NMDA receptor has been strongly implicated in memory, but research to date on the effects of NMDA antagonists has examined only some aspects of human memory functions. This study used a double-blind, placebo-controlled, independent groups design with 54 healthy volunteers to examine the effects of infusions of two doses (0.4, 0.8 mg/kg) of the NMDA antagonist ketamine upon the five human memory systems, aspects of executive functioning and schizophrenia-like and dissociative symptoms. Ketamine produced a dose-dependent impairment to episodic and working memory and a slowing of semantic processing. Ketamine also impaired recognition memory and procedural learning. Attention, perceptual priming and executive functioning were not affected following the drug. In addition, ketamine induced schizophrenia-like and dissociative symptoms, which were not correlated with the cognitive measures. These data suggest that, in humans, ketamine produces a selective pattern of impairments to working, episodic, and procedural memory but not to perceptual priming, attention or aspects of executive functioning.
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PMID:Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers. 1460 67

N-methyl-D-aspartate (NMDA) antagonists produce behavioral and electrophysiological effects similar to schizophrenia. The mouse P20, N40, and P80 event related potential (ERP) components were analyzed for genetic variance among inbred strains and ketamine-induced differences to model abnormalities in the P50, N100, and P200 in schizophrenia. Ketamine increased P20/N40 amplitude and decreased P80 amplitude. Therefore, the effects of ketamine in mice are inconsistent with alterations in the corresponding P50 and N100 in schizophrenia, suggesting that NMDA receptor dysfunction may not underlie abnormalities of these components in schizophrenia. However, the effects of ketamine on the mouse P80 were consistent with P200 ERP changes in schizophrenia and support the hypothesis that NMDA dysfunction may contribute to some neuronal abnormalities in schizophrenia. The current study lays the groundwork for defining the role of NMDA-mediated transmission for specific aspects of neuronal processing that vary with genetic background. Future studies could use transcription profiling to clarify such interactions between genetic background, specific neuronal circuits, and transmitter systems.
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PMID:The effects of ketamine vary among inbred mouse strains and mimic schizophrenia for the P80, but not P20 or N40 auditory ERP components. 1517 75

Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) may be involved in the pathophysiology of schizophrenia. NMDAR antagonists like ketamine induce schizophrenia-like features in humans. In rodent studies, NMDAR antagonism impairs learning by disrupting long-term potentiation (LTP) in the hippocampus. This study investigated the effects of ketamine on spatial learning (acquisition) vs retrieval in a virtual Morris water task in humans. Verbal fluency, working memory, and learning and memory of verbal information were also assessed. Healthy human subjects participated in this double-blinded, placebo-controlled study. On two separate occasions, ketamine/placebo was administered and cognitive tasks were assessed in association with behavioral ratings. Ketamine impaired learning of spatial and verbal information but retrieval of information learned prior to drug administration was preserved. Schizophrenia-like symptoms were significantly related to spatial and verbal learning performance. Ketamine did not significantly impair attention, verbal fluency, or verbal working memory task performance. Spatial working memory was slightly impaired. In conclusion, these results provide evidence for ketamine's differential impairment of verbal and spatial learning vs retrieval. By using the Morris water task, which is hippocampal-dependent, this study helps bridge the gap between nonhuman animal and human NMDAR antagonism research. Impaired cognition is a core feature of schizophrenia. A better understanding of NMDA antagonism, its physiological and cognitive consequences, may provide improved models of psychosis and cognitive therapeutics.
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PMID:Selective cognitive impairments associated with NMDA receptor blockade in humans. 1564 51

Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ketamine, dizocilpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2High, their dissociation constants (Ki) were obtained on [3H]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2High with a Ki of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a Ki of 313 nM, as labeled by [3H]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2High with a Ki of 55 nM, an affinity higher than its 3100 nM Ki for the NMDA sites. Dizocilpine had a Ki of 0.3 nM at D2High, but a Kd of 1.8 nM at the NMDA receptor. LSD had a Ki of 2 nM at D2High. Because the psychotomimetics had higher potency at D2High than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis.
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PMID:Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. 1585 61


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