Model Psychoses and Schizophrenia

A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine (Paschen 1996) and schizophrenia (Javitt and Zukin 1991;Henn 1995;Olney and Farber 1995).In schizophrenia, a role for excitatory amino acids and NMDA receptors was suggested when NMDA receptor antagonists, such as phencyclidine (PCP) and ketamine, were found to induce symptoms resembling the positive and negative symptoms of schizophrenia in healthy subjects and exacerbate such symptoms in patients with schizophrenia (Luby et al. 1962;Javitt and Zukin 1991;Krystal et al. 1994;Lahti et al. 1995;Malhotra et al. 1997b). A hypofunction of the glutamatergic system and NMDA receptors has been hypothesized in schizophrenia (for review, see Olney and Farber 1995) and appears to be supported by post-mortem studies (Nishikawa et al. 1983;Toru et al. 1988;Ishimaru et al. 1994;Tsai et al. 1995). If schizophrenic symptoms are the result of the diminished functioning of NMDA receptors, stimulation of these receptors could be beneficial for patients with schizophrenia. Glycine and D-cycloserine stimulate the strychnine-insensitive glycine recognition site of the NMDA receptor and, by inference, may ameliorate schizophrenic symptoms. Some studies have used glycine for this purpose. In a double-blind, parallel, placebo-controlled study with seven patients in each group, glycine treatment during 8 weeks in a dose ‫ف‬ 30 grams daily, added to typical antipsychotics, selectively reduced the scores on the negative symptom subscale of the Positive and Negative Symptoms Scale (PANSS) (Javitt et al. 1994). A similar result has also been reported in 11 schizophrenic patients using glycine in dosages between 40 and 80 grams daily in a doubleblind crossover design with treatment periods of 6 weeks (Heresco-Levy et al. 1996). These two studies suggest that stimulation of the NMDA receptor may ameliorate the negative symptoms of schizophrenia.As a treatment of schizophrenic symptoms, glycine's major limitation is its limited access to the central nervous system (CNS). Contrary to glycine, the partial NMDA agonist D-cycloserine, an antibiotic used in the treatment of tuberculosis (Walker and Murdoch 1957), rapidly passes the blood-brain barrier and may therefore be more suitable for the treatment of patients with schizophrenia than glycine. However, D-cycloserine acts as a partial agonist of the NMDA receptor, with around 60%-90% of the agonistic efficacy of glycine (Chessell et al. 1991;Priestley et al. 1995) and with between 6 to 20 times less affinity for the glycine recognition site of the NMDA receptor than glycine (Ishimaru et al. 1994;Priestley et al. 1995)...

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D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics A Double-Blind, Parallel, Placebo-Controlled Study

Berckel¹

1999

“…Ketamine, a PCP analog still used in human anesthesia, has been reported to cause reactions similar to but not as severe as those caused by PCP, including brief, reversible "positive" and "negative" schizophrenia-like symptoms (Krystal et al 1994;Malhotra et al 1996). Both PCP and ketamine can exacerbate psychosis in schizophrenia Luby et al 1962;Lahti et al 1995a;Lahti et al 1995b;Malhotra et al 1997). …”

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“…Early investigators characterized a PCP-induced clinical syndrome of schizophrenia-like symptoms, including hallucinations, delusions, idiosyncratic and illogical thinking, poverty of speech and thought, agitation, disturbances of emotion, affect, withdrawal, decreased motivation, and dissociation (Johnstone et al 1959;Luby et al 1959;Rosenbaum et al 1959;Luby et al 1962;Corssen and Domino 1966;Bakker and Amini 1961;Davies and Beech 1960;Domino and Luby 1981). This PCP-induced syndrome can be indistinguishable from acute presentations of schizophrenia (Yesavage and Freeman 1978;Erard et al 1980).…”

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Ketamine-Induced NMDA Receptor Hypofunction as a Model of Memory Impairment and Psychosis

Newcomer

Farber

Jevtović-Todorović

et al. 1999

546

350

Considerable research interest has recently been focused on the role of glutamate and related neural circuitry in the neurobiology of schizophrenia. The results of these investigations have emphasized hypofunction of glutamatergic neurons and/or the N-methyl-D-aspartate (NMDA) glutamate receptor (Tsai et al. 1995;Kim et al. 1980aKim et al. , 1980bSherman et al. 1991;Deutsch et al. 1989;Javitt and Zukin 1991;Olney 1988a;Olney 1988b;Olney and Farber 1995). An important element of several of these theoretical positions is that NMDA receptor hypofunction (NRH) produced by any mechanism can be psychotogenic. This has renewed interest in the clinical effects of NMDA glutamate receptor antagonists.Ketamine and phencyclidine (PCP) are non-competitive NMDA glutamate receptor antagonists (Zukin and Zukin 1979;Vincent et al. 1979;Lodge and Anis 1982;Lodge et al. 1987) which can produce a transient state of NRH in the brain. Early investigators characterized a PCP-induced clinical syndrome of schizophrenia-like Received March 18, 1998; revised June 19, 1998; accepted June 29, 1998. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 20 , NO . 2 NMDA Receptor Hypofunction Induced Memory Decrease 107 symptoms, including hallucinations, delusions, idiosyncratic and illogical thinking, poverty of speech and thought, agitation, disturbances of emotion, affect, withdrawal, decreased motivation, and dissociation (Johnstone et al. 1959;Luby et al. 1959;Rosenbaum et al. 1959;Luby et al. 1962;Corssen and Domino 1966;Bakker and Amini 1961;Davies and Beech 1960;Domino and Luby 1981). This PCP-induced syndrome can be indistinguishable from acute presentations of schizophrenia (Yesavage and Freeman 1978;Erard et al. 1980). Ketamine, a PCP analog still used in human anesthesia, has been reported to cause reactions similar to but not as severe as those caused by PCP, including brief, reversible "positive" and "negative" schizophrenia-like symptoms (Krystal et al. 1994;Malhotra et al. 1996). Both PCP and ketamine can exacerbate psychosis in schizophrenia Luby et al. 1962;Lahti et al. 1995a;Lahti et al. 1995b;Malhotra et al. 1997).Declarative, explicit or secondary memory and learning deficits in patients with schizophrenia occur early in the course of the illness and are quantitatively large compared with deficits in other differentiated elements of cognitive performance, showing stability "on" versus "off" antipsychotic medication and over repeated testing (Gruzelier et al. 1988;Saykin et al. 1991Saykin et al. , 1994Cannon et al. 1994). Clinical and preclinical investigations suggest the hypothesis that changes in NMDA glutamate receptor activity in patients with schizophrenia may be causally related to memory impairments found in this disorder. Relevant to this hypothesis, the activation of post-synaptic NMDA receptors is important for the induction of the activity-dependent synaptic modification called long-term potentiation (LTP) (Bliss and Collingridge 1993;Collingridge and Bliss 1995), and hippocampal LTP has been postulated to underlie cert...

“…Perhaps the strongest evidence for glutamatergic involvement in this illness is that dissociative anesthetics, especially phencyclidine and ketamine, can cause a schizophreniform psychosis in normal humans, and worsen psychotic symptoms in persons with schizophrenia (Itil et al 1967;Javitt and Zukin 1991;Krystal et al 1994;Lahti et al 1995;Luby et al 1962). These drugs are uncompetitive inhibitors of the NMDA subtype of glutamate receptor, suggesting that schizophrenia may be associated with decreased NMDA receptor activity (Javitt and Zukin 1991;Carlsson and Carlsson 1990).…”

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Abnormal Kainate Receptor Expression in Prefrontal Cortex in Schizophrenia

Meador‐Woodruff

2001

A growing literature suggests glutamatergic dysfunction in schizophrenia. Perhaps the strongest evidence for glutamatergic involvement in this illness is that dissociative anesthetics, especially phencyclidine and ketamine, can cause a schizophreniform psychosis in normal humans, and worsen psychotic symptoms in persons with schizophrenia (Itil et al. 1967;Javitt and Zukin 1991;Krystal et al. 1994;Lahti et al. 1995;Luby et al. 1962). These drugs are uncompetitive inhibitors of the NMDA subtype of glutamate receptor, suggesting that schizophrenia may be associated with decreased NMDA receptor activity (Javitt and Zukin 1991;Carlsson and Carlsson 1990). Further, facilitators of NMDA receptor activity have been shown to improve psychotic symptoms. Since direct agonists of this receptor are neurotoxic, other therapeutic strategies have been used to enhance NMDA receptor activity. Agonists at the glycine co-agonist site of the NMDA receptor have been found to improve negative psychotic symptoms, providing additional support for diminished NMDA receptor activity in schizophrenia (Goff et al. 1995;Goff et al. 1999;Heresco-Levy et al. 1999;Javitt et al. 1994).In addition to the NMDA subtype, however, there NO . 5 are additional families of cation-selective ionotropic glutamate receptors, the AMPA and kainate subtypes. Although the NMDA receptor is the subtype of glutamate receptor usually implicated in schizophrenia, the other ionotropic glutamate receptors also may be abnormal in this illness; abnormalities. While a growing literature suggests abnormal expression of both NMDA and AMPA receptors in the brain in schizophrenia (reviewed in Meador-Woodruff and Healy 2000), much less is known about potential abnormalities of the kainate receptor in this illness. The ionotropic glutamate receptors share a common structural motif, and are each composed of four or five family-specific subunits that form ligandgated ion channels (Hollmann and Heinemann 1994). Kainate receptors are composed of the low affinity gluR5, gluR6, and gluR7 subunits, and the high affinity KA1 and KA2 subunits (Hollmann and Heinemann 1994). The gluR5, gluR6, and gluR7 subunits assemble into homomeric complexes, or heteromerically coassemble with KA1 and KA2, resulting in receptors with distinct pharmacological properties, suggesting that subunit composition, at least in part, determines the functional properties of the kainate receptor (Lerma 1998).Only several studies have examined the kainate-associated subunits in schizophrenic brain. Decreased expression of gluR6 and KA2 mRNA were noted in several hippocampal regions, although gluR6 mRNA was not found to be changed in the cerebellum in schizophrenia in this same study (Porter et al. 1997). A recently published study suggested that gluR7 and KA1 subunit transcripts are decreased in the superior frontal gyrus in schizophrenics, similar to decreases also noted by this investigator for some of the subunits associated with the AMPA and NMDA receptors (Sokolov 1998). Only one study to date has examine...