Schizophrenia ketamine

PCP binds to a site within the ion channel of the NMDA receptor that blocks the influx of cations, thereby acting as a non-competitive antagonist. PCP produces a syndrome in normal individuals that closely resembles schizophrenia and exacerbates symptoms in patients with chronic schizophrenia. Ketamine is an anesthetic that has approximately a 10- to 15-fold lower affinity for the NMDA receptor, and it produces the characteristic cognitive deficits of schizophrenia. When ketamine is administered to patients with schizophrenia stabilized with antipsychotic medication, it produces delusions, hallucinations, and thought disorder, consistent with the patient s typical pattern of psychotic relapse. Consistent with this model, chronic PCP administration also increases subcortical dopamine release, particularly in the nucleus accumbens, emphasizing the reciprocal modulation of the glutamate and dopamine neuronal systems in schizophrenia. 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

Controlled clinical investigations with careful titration of doses in normal subjects demonstrate that ketamine produces negative symptoms, such as withdrawal and the subtle cognitive impairments associated with schizophrenia [25]. As is the case for schizophrenia, these symptoms occur without clouding of consciousness or frank dementia. Positive symptoms with auditory hallucinations and fully... 

Other hallucinogenic drugs including substances related to LSD are mentioned under delirium. Phencyclidine and ketamine can also produce similar hallucinatory states without delirium including time distortion, distortion of body image, synaesthesia, visual hallucinations, depersonalisation, derealisation, paranoid ideation and a schizophreniform psychosis which includes the negative symptoms of schizophrenia (Gorelick Balster, 1995). 

Abnormalities of the glutamate system have also been documented in neuropsychiatric disorders. For example, compounds such as PCP and ketamine, which block the NMDA receptor, can induce psychotic symptoms. By contrast, compounds such as d-cycloserine or glycine, which increase NMDA receptor function via the glycine binding site, can decrease psychotic and/or negative symptoms in schizophrenia (Farber et ah, 1999 Goff et ah, 1999, Fleresco-Levy et ah, 1999). 

Glutamate was initially implicated in schizophrenia by studies of the behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., PCP, ketamine), which produce psychotic symptoms and cognitive dysfunction in healthy subjects and exacerbate psychotic, negative, and cognitive symptoms in patients with schizophrenia. Studies show that acute administration of NMDA antagonists causes NMDA receptor dysfunction, resulting in decreased inhibition of subcortical dopamine neurons and consequent increased mesolimbic dopamine release. Chronic administration produces decreased release, or hypoactivity, of dopamine in the prefrontal cortex (Davis and Lieberman, 2000). 

Mean SD of DLPFC ["C]NNC 112 BP (ml/g). Left patients with schizophrenia (SCH) compared to controls (CTR). Right healthy controls (white bars) versus chronic ketamine users (CKU) (gray bars)... 

In initial studies with PCP and ketamine in the early 1960s, it was noted that both agents produced what would now be considered positive, negative, and cognitive symptoms of schizophrenia (Luby et al., 1962 Javitt and Zukin, 1991). Similar results were observed in the clinical studies of PCP abusers in the early 1980s. 

Symptomatic effects of NMDA blockade were better classified starting in the early 1990s in a series of ketamine challenge studies conducted in both normal volunteers and schizophrenia patients. In normal volunteers, significant increases in positive, negative, and cognitive symptoms were observed in schizophrenia, using scales such as the PANSS or BPRS/SANS. 

A potentially informative difference between ketamine-induced symptoms and those of schizophrenia is in the production of hallucinations. Thus, in established schizophrenia, auditory hallucinations consisting of voices of various types are common, whereas visual hallucinations are rare. In contrast, during ketamine-induced psychosis, visual perceptual distortions are common but organized auditory... 

Geyer et al., 2001) and primate (Linn et al., 2003) models. In contrast, ketamine appears to have little effect on either PPI or P50 gating in normal human volunteers ( Table 1.3-2). The basis for the dissociation between animal and human studies is unknown. However, these findings suggest that gating deficits in schizophrenia may reflect primarily nonglutamatergic pathology. 

This alternative model of schizophrenia, based upon actions of PCP and ketamine, was also proposed in the late 1980s (Olney, 1989 Olney et al., 1989), but focuses on a separate aspect of action of NMDA antagonists. In addition to producing cognitive dysfunction, NMDA antagonists were observed to produce neurode-generative changes in specific populations of cortical pyramidal neurons, particularly in frontal, posterior... 

Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiat 156 1646-1649. 

---