Clinical schizophrenia & related psychoses
October 1, 2010
Joshua T Kantrowitz, Daniel C Javitt
Schizophrenia has long been understood as a disorder of dopamine neurotransmission, but this framework has limited research to dopamine-rich brain regions. About twenty years ago, an alternative model emerged based on how dissociative anesthetics like PCP and ketamine induce psychosis by blocking NMDA-type glutamate receptors. Unlike dopamine, glutamate is widespread in the brain and central to sensory processing and cortical analysis, suggesting that schizophrenia involves diffuse but process-specific cortical dysfunction. NMDA receptors also interact with other neurotransmitter systems and have binding sites for endogenous compounds like glycine and D-serine. This glutamatergic theory opens new treatment approaches, many now entering clinical evaluation.
Novartis Foundation symposium
January 1, 2008
Daniel C Javitt
Schizophrenia affects up to 1% of the global population. While traditional models focused on dopamine dysfunction, glutamatergic models have become mainstream over the last 15 years, explaining features poorly accounted for by dopamine alone. These models are based on observations that PCP and ketamine induce psychotic symptoms by blocking NMDA-type glutamate receptors. NMDA receptors are widespread, causing information-processing deficits in sensory and subcortical systems as well as higher cortical regions. They also regulate dopamine release, suggesting dopaminergic deficits may be secondary to glutamatergic dysfunction. Agents stimulating glutamatergic transmission, such as glycine-site agonists and glycine transport inhibitors, have shown promise in preclinical studies and are undergoing clinical development, potentially leading to new treatments.
Psychopharmacology
May 1, 2007
Gary S Linn, Robert T O'Keeffe, Kenneth Lifshitz et al.
Glycine treatment reversed the effects of the dissociative anesthetic PCP on stereotyped pacing in socially housed monkeys but had no effect on scanning behavior. Chronic PCP infusion in ten monkeys produced behavioral symptoms modeling both positive and negative symptoms of schizophrenia. Eight of ten animals experienced extreme motoric and physiological episodes during stressful events. The results suggest glycine may be beneficial for negative symptoms of schizophrenia, and that chronic PCP in primates could serve as a model for developing drugs targeting schizophrenia symptoms.
International review of neurobiology
January 1, 2007
Daniel C Javitt
Schizophrenia affects up to 1% of the population worldwide. The dopamine hypothesis has been the leading neurochemical explanation, proposing that excess dopamine in striatal regions and deficits in prefrontal regions cause symptoms. About 15 years ago, an alternative model emerged based on the observation that drugs like PCP and ketamine, which block NMDA-type glutamate receptors, induce psychotic and cognitive symptoms similar to schizophrenia. Since then, evidence has accumulated supporting NMDA receptor hypofunction in schizophrenia. NMDA antagonists produce negative and cognitive symptoms as well as positive ones, unlike dopaminergic agents. Treatment studies with NMDA modulators such as glycine, d-serine, and glycine transport inhibitors have shown encouraging but controversial results. Genetic and neurochemical studies point to causes of NMDA dysfunction.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2003
Andrea Balla, Henry Sershen, Michael Serra et al.
Dopaminergic hyperactivity in the prefrontal cortex (PFC) may contribute to cognitive dysfunction in schizophrenia. In rats, subchronic treatment with phencyclidine (PCP) at doses of 10 mg/kg/day or higher produced serum concentrations associated with PCP psychosis in humans. PCP-treated rats showed a significant, dose-dependent enhancement in amphetamine-induced dopamine release in the PFC but not in the nucleus accumbens (NAc), along with increased locomotor activity. This enhanced response appeared after 3 days of treatment, persisted through 14 days, and resolved within 4 days of withdrawal. The findings suggest that NMDA receptor dysfunction could underlie the dopaminergic abnormalities seen in schizophrenia and that even short-term PCP abuse may potentiate the effects of psychostimulants.