Article

Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology

University of Maryland, Baltimore, Baltimore, Maryland, United States
Neuropsychopharmacology (Impact Factor: 7.05). 10/2001; 25(4):455-67. DOI: 10.1016/S0893-133X(01)00243-3
Source: PubMed

ABSTRACT

This study evaluates the effects of ketamine on healthy and schizophrenic volunteers (SVs) in an effort to define the detailed behavioral effects of the drug in a psychosis model. We compared the effects of ketamine on normal and SVs to establish the comparability of their responses and the extent to which normal subjects might be used experimentally as a model. Eighteen normal volunteers (NVs) and 17 SVs participated in ketamine interviews. Some (n = 7 NVs; n = 9 SVs) had four sessions with a 0.1-0.5 mg/kg of ketamine and a placebo; others (n = 11 NVs; n = 8 SVs) had two sessions with one dose of ketamine (0.3 mg/kg) and a placebo. Experienced research clinicians used the BPRS to assess any change in mental status over time and documented the specifics in a timely way. In both volunteer groups, ketamine induced a dose-related, short (<30 min) increase in psychotic symptoms. The scores of NVs increased on both the Brief Psychiatric Rating Scale (BPRS) psychosis subscale (p =.0001) and the BPRS withdrawal subscale (p =.0001), whereas SVs experienced an increase only in positive symptoms (p =.0001). Seventy percent of the patients reported an increase (i.e., exacerbation) of previously experienced positive symptoms. Normal and schizophrenic groups differed only on the BPRS withdrawal score. The magnitude of ketamine-induced changes in positive symptoms was similar, although the psychosis baseline differed, and the dose-response profiles over time were superimposable across the two populations. The similarity between ketamine-induced symptoms in SVs and their own positive symptoms suggests that ketamine provides a unique model of psychosis in human volunteers. The data suggest that the phencyclidine (PCP) model of schizophrenia maybe a more valid human psychosis/schizophrenia drug model than the amphetamine model, with a broader range of psychotic symptoms. This study indicates that NVs could be used for many informative experimental psychosis studies involving ketamine interviews.

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Available from: Carol Tamminga, Aug 29, 2015
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    • "The administration of NMDAR antagonists, such as phencyclidine and ketamine , to normal individuals results in symptoms that closely resemble those seen in schizophrenia (Javitt and Zukin 1991; Krystal et al. 1994). Furthermore, NMDAR antagonists exacerbate symptoms in patients with schizophrenia (Lahti et al. 2001). The epitope targeted by anti-NMDAR antibodies is located in the extracellular domain of the GluN1 subunit (Dalmau et al. 2008; Gleichman et al. 2012). "
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    ABSTRACT: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is now widely recognized and the patients with this disease show prominent psychiatric symptoms followed by seizures, respiratory failure, involuntary movement, autonomic instability, and amnesia. The anti-NMDAR antibody titer coincides with disease activity, and antibody-deprivation treatment ameliorates neurological symptoms. Previous studies have shown that clusters of NMDARs on the neuronal surface decrease in density upon incubation with the cerebrospinal fluid from patients (NMDAR-CSF), and that the induction of long-term potentiation, a cellular mechanism underlie learning and memory processes, was suppressed with NMDAR-CSF. In this study, we exposed mice to NMDAR-CSF in an attempt to reproduce the human symptoms in mice. CSF was continuously administered via a cannula placed in the lateral ventricle of the mouse that connected to an osmotic pump transplanted in the back of the mouse. From day 8-18, we evaluated the behavior of the mice using standardized tests that were performed serially. Mice exposed to NMDAR-CSF showed impaired spatial memory, as detected with the Morris water maze test. Brain tissue from mice with memory disturbances had decreased content of NMDAR protein in the hippocampal area shown by immunohistochemistry, which is consistent with the anti-NMDAR antibodies affect the expression and function of NMDARs, resulting in anti-NMDAR encephalitis-like symptoms. Also, the mice treated with the NMDAR-CSF did not show inflammatory cell infiltration or neuron loss in their brain tissue and this lack of nervous tissue destruction is encouraging as it is consistent with the idea that this disease can be treated through immunotherapy.
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    • "In particular, hypofunction of the N-methyl-D-aspartate receptor (NMDA-R) is hypothesized to play a key role in the pathophysiology of this disease (Coyle et al., 2003; Paz et al., 2008). For example, antagonists of NMDA-R, phencyclidine (PCP), MK-801 and ketamine , induce schizophrenia-like symptoms, that is, positive and negative symptoms, and cognitive dysfunction in normal patients (Javitt and Zukin, 1991; Jentsch and Roth, 1999; Lahti et al., 2001; Newcomer et al., 1999) and increased psychosis in patients with schizophrenia (Lahti et al., 1995, 2001). "

    Full-text · Dataset · Jul 2015
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    • "In particular, hypofunction of the N-methyl-D-aspartate receptor (NMDA-R) is hypothesized to play a key role in the pathophysiology of this disease (Coyle et al., 2003; Paz et al., 2008). For example, antagonists of NMDA-R, phencyclidine (PCP), MK-801 and ketamine , induce schizophrenia-like symptoms, that is, positive and negative symptoms, and cognitive dysfunction in normal patients (Javitt and Zukin, 1991; Jentsch and Roth, 1999; Lahti et al., 2001; Newcomer et al., 1999) and increased psychosis in patients with schizophrenia (Lahti et al., 1995, 2001). "

    Full-text · Dataset · Jul 2015
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