Archives of General Psychiatry
December 1, 2000
Daniel Umbricht, Liselotte Schmid, Rene Koller et al.
590 citations
In healthy volunteers, the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine significantly reduced the amplitude of mismatch negativity (MMN) brain responses to pitch and duration changes by 27% and 21%, respectively. Ketamine also impaired performance on a continuous performance test, decreasing hit rates and increasing specific context-dependent errors (BX errors), indicating a failure to form and use transient memory traces. These findings suggest that NMDARs are critically involved in generating MMN and that NMDAR dysfunction may underlie deficits in transient memory at different levels of information processing in schizophrenia.
bioRxiv Preprint Server
August 12, 2022
Daniel C Javitt, Jonathan C. Javitt
preprint
D-cycloserine (DCS) did not substitute for ketamine in ketamine-dependent rats, suggesting low abuse potential. The study used a self-administration paradigm to evaluate whether DCS would be self-administered by rats trained to self-administer ketamine. DCS failed to maintain ketamine-reinforced behavior, indicating it lacks the reinforcing properties associated with abuse liability. This finding contrasts with NMDAR antagonist antidepressants, which have known potential for abuse. The results suggest DCS may have a lower risk of addiction compared to other drugs in its class.
Schizophrenia Bulletin
September 1, 2012
Daniel C Javitt, Stephen R Zukin, Uriel Heresco-Levy et al.
Over the past 20 years, glutamatergic models of schizophrenia have gained acceptance, based on phencyclidine (PCP) inducing psychosis by blocking NMDA-type glutamate receptors. This review examines two predictions: neurocognitive deficits in schizophrenia should mirror those from NMDAR dysfunction, and agents stimulating NMDAR function should be therapeutic. Studies show severe sensory dysfunction in schizophrenia, including impaired mismatch negativity and visual P1 potentials, similar to deficits from NMDAR antagonists like ketamine. Sensory dysfunction predicts impairments in higher-order cognition like emotion recognition. Treatment studies with glycine-site compounds (glycine, D-serine, D-cycloserine) and glycine transport inhibitors (RG1678) show significant beneficial effects on persistent symptoms, suggesting novel treatment and prevention approaches.
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.