Schizophrenia phencyclidine

Phencyclidine (PCP), a dissociative anesthetic agent, which is subject to abuse, produces behavioral effects in man that frequently resemble schizophrenia (Luisada 1978). Manifestations of persistent psychopathology frequently remain after the acute effects of PCP have diminished. With PCP, subjects may display autistic and delusional thinking typical of schizophrenics (Luby et al. 1959). A more striking link between schizophrenia and PCP comes from observations of cases in which PCP was given to hospitalized schizophrenics (Luisada 1978). After receiving PCP, these patients showed extreme exacerbation of their psychoses the reaction persisted for up to 6 weeks. By contrast, LSD produced no more severe effects in schizophrenics than in normal subjects. 

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. 

Phencyclidine (PCP) psychosis faithfully masquerades as schizophrenia, though some say it resembles mania. PCP is discovered to block NMDA subtypes of glutamate receptors. Glycine and cycloserine, which stimulate NMDA receptors, are antipsychotic. 

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). 

Glutamate systems have long been implicated in the pathophysiology of schizophrenia. Strong if circumstantial evidence comes from the psychosis associated with phencyclidine (PGP) administration PGP blocks of the ion channel the glutamate/NMDA receptor. Psychosis due to PGP and other noncompetitive NMDA antagonists includes the development of negative as well as positive symptoms and therefore is considered a better model of schizophre-... 

Sams-Dodd, F. Phencyclidine-induced stereotyped behaviour and social isolation in rats a possible animal model of schizophrenia. Behav. Pharmacol. 7 3-23. 1996. 

Javitt, D. C., and Frusciante, M. (1997). Glycyldodecylamide, a phencyclidine behavioral antagonist, blocks cortical glycine uptake Implications for schizophrenia and substance abuse. Psychopharma-cologji 129, 96-98. 

Glutamate and Schizophrenia Phencyclidine, jV-methyl-D-aspartate Receptors, and Dopamine—Glutamate Interactions Daniel C. Javitt... 

Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991 148 1301-1308. 

Jentsch JD, Roth RH. 1999. The neuropsychopharmacology of phencyclidine From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20 201-225. 

Attention first turned to glutamatergic systems, with the observation that that phencyclidine (PCP) and similarly acting psychotomimetic compounds induced their unique behavioral effects by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors (Javitt, 1987 Olney, 1989 Javitt and Zukin, 1991 Coyle, 1996). The ability of these compounds to transiently reproduce the key symptoms of schizophrenia by blocking NMDA receptors led to the concept that symptoms in schizophrenia may reflect the underlying dysfunction or dysregulation of NMDA receptor-mediated neurotransmission. 

Domino E, Luby E. 1981. Abnormal mental states induced by phencyclidine as a model of schizophrenia. PCP (Phencyclidine) Historical and Current Perspectives. Domino E, editor. Ann Arbor, Michigan NPP Books. 

Javitt DC. 1987. Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J Clin Psychiatry 9 12-35. 

Javitt DC. 2007. Glutamate and schizophrenia Phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol 78 69-108. 

Olney JW, Farber NB. 1995. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52 998-1007. Olney JW, Labruyere J, Price MT. 1989. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244 1360-1362. 

Reynolds LM, Cochran SM, Morris BJ, Pratt JA, Reynolds GP. 2005. Chronic phencyclidine administration induces schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate in rat brain. Schizophr Res 73 147-152. 

The glutamate hypofunction hypothesis relies on the fact that phencyclidine and ketamine, both potent noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonists, induce schizophrenia-like symptoms in healthy individuals and worsen some symptoms in schizophrenia patients... 

---