Behavioral effects schizophrenia

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. 

The close resemblance between schizophrenia and PCP-induced psychosis suggests that the behavioral effects produced by PCP might be useful as a model of psychosis. On this basis, most animal studies have examined the ability of various agents to modify PCP-induced hyperactivity and stereotypy. While some studies suggest that neuroleptics such as haloperidol (Castellani and Adams 1981 Garey et al. 1980), chlorpromazine, or clozapine (Freed et al. 

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). 

Clozapine has been found effective in patients who did not improve during treatment with first-generation antipsychotics, and since the hematological side effects permit only its restricted use, this dmg has a unique indication for treatment- resistanf schizophrenia. Another unique indication for clozapine is the reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders. The indications of clozapine and its two analogues, olanzapine and quetiapine, are summarized in Tab. 13.5. The US labels of these drugs served as the data source [62-64]. Clozapine and olanzapine, but not quetiapine, are available in intramuscular form, which is helpful in the treatment of acutely agitated patients with diagnoses as defined in Tab. 13.5. 

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. 

Haloperidol was discovered in the Janssen Laboratories in 1958 (280,315,320,322). It is a butyrophenone derivative and was pursued because of its ability to block the behavioral activating effects of amphetamine in rat models. The amphetamine models were used as screening tools, because symptoms observed in paranoid schizophrenia were noted to be similar to those that developed in chronic amphetamine abusers. The behavioral profile of haloperidol was qualitatively similar to that of CPZ, but haloperidol required up to 50-fold lower doses to exert the same behavioral effects as CPZ. Around this time, the term "major tranquilizer" began to be replaced by the term "neuroleptic." The compound was pursued very vigorously, and the initial clinical results were published only 10 months after the initial synthesis of the compound. Haloperidol is still one of the most widely pre-... 

Behavioral effects of PCP range from sleep to catatonic detachment to paranoid psychosis to violent hostility. Users are sometimes amnestic for events that occur under the influence of the drug. Psychoses sometimes last for weeks. Users with a previous history of schizophrenia are especially susceptible to the psychotomimetic effects of the drug. The only truly characteristic behavioral effect of PCP use is its high unpredictability. The signs and symptoms of PCP intoxication are summarized in Table 64-4. 

This hypothesis is further supported by the similarities between the behavioral effects caused by the administration of N-methyl-o-aspartate (NMDA) receptor antagonists to human subjects and the clinical symptoms of schizophrenia. Moreover, clinical trials in which NMDA receptor activity was enhanced by agents acting at the glycine modulatory site have demonstrated decreases in negative symptoms and variable improvements in cognitive function. There are also data from postmortem studies suggesting alterations in... 

---