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D C Javitt

Publications and source records attributed to D C Javitt.

At least 55 records · Page 3Linked to original sources
PubMed1999

Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.

BACKGROUND: Disturbances of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission may play an important role in the pathophysiology of negative symptoms of schizophrenia. Glycine, a small nonessential amino acid, functions as an obligatory coagonist at NMDA receptors through its action at a strychnine-insensitive binding site on the NMDA receptor complex. Glycine-induced augmentation of NMDA receptor-mediated neurotransmission may thus offer a potentially safe and feasible approach for ameliorating persistent negative symptoms of schizophrenia. METHODS: Twenty-two treatment-resistant schizophrenic patients participated in a double-blind, placebo-controlled, 6-week, crossover treatment trial with 0.8 g/kg per day of glycine added to their ongoing antipsychotic medication. Clinical assessments, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Simpson-Angus Scale for Extrapyramidal Symptoms, and the Abnormal Involuntary Movement Scale, were performed biweekly throughout the study. Clinical laboratory values and amino acid serum levels were monitored. RESULTS: Glycine treatment was well tolerated and induced increased glycine (P=.001) and serine (P=.001) serum levels. Glycine administration resulted in (1) a significant (P<.001) 30%+/-16% reduction in negative symptoms, as measured by the PANSS, and (2) a significant (P<.001) 30%+/-18% improvement in the BPRS total scores. The improvement in negative symptoms was unrelated to alterations in extrapyramidal effects or symptoms of depression. Low pretreatment glycine serum levels significantly predicted (r= 0.80) clinical response. CONCLUSION: These findings support hypoglutamatergic hypotheses of schizophrenia and suggest a novel approach for the pharmacotherapy of negative symptoms associated with this illness.

Adult↗
PubMed1999

Treatment of negative and cognitive symptoms.

Persistent negative symptoms and cognitive dysfunction are a major cause of chronic disability in schizophrenia. Atypical antipsychotics such as clozapine, risperidone, and olanzapine induce significantly greater improvement in negative symptoms than that which is obtained with conventional agents. However, it remains unclear whether these agents treat core negative symptoms of schizophrenia, or simply induce less secondary psychopathology. A second approach for treatment of persistent negative symptoms is the use of N-methyl-d-aspartate (NMDA) receptor-stimulating agents, such as glycine, d-serine or d-cycloserine. These agents, when added to conventional or atypical antipsychotics, may induce significant additional reduction in both negative and cognitive symptoms.

Antimetabolites↗
PubMed1999

Normal time course of auditory recognition in schizophrenia, despite impaired precision of the auditory sensory ("echoic") memory code.

Prior studies have demonstrated impaired precision of processing within the auditory sensory memory (ASM) system in schizophrenia. This study used auditory backward masking to evaluate the degree to which such deficits resulted from impaired overall precision versus premature decay of information within the short-term auditory store. ASM performance was evaluated in 14 schizophrenic participants and 16 controls. Schizophrenic participants were severely impaired in their ability to match tones following delay. However, when no-mask performance was equated across participants, schizophrenic participants were no more susceptible to the effects of backward maskers than were controls. Thus, despite impaired precision of ASM performance, schizophrenic participants showed no deficits in the time course over which short-term representations could be used within the ASM system.

Acoustic Stimulation↗
PubMed1999

Panmodal processing imprecision as a basis for dysfunction of transient memory storage systems in schizophrenia.

Schizophrenia is a severe mental disorder associated with cognitive disturbances that may reflect underlying deficits in the functioning of brain transient memory storage systems. This study investigates performance in three distinct tasks that require transient memory storage: (1) tone discrimination, (2) object weight discrimination, and (3) "AX"-type visual continuous performance task. The tests used were chosen to investigate the degree to which a similar pattern of performance deficit could be observed across multiple sensory and cognitive domains in schizophrenia. In each of the paradigms, a similar pattern emerged: subjects with schizophrenia showed severe performance deficits whenever performance depended on functioning of transient memory systems. The deficits were apparent at both short and long interstimulus intervals (ISI), however, and schizophrenia subjects were no more affected by increasing ISI than were controls. Moreover, when short ISI performance was matched across groups by manipulating task difficulty, subsequent decay in performance was equivalent across groups. Thus, although schizophrenia subjects show severe performance deficits in memory-dependent tasks, the deficits do not appear to reflect impaired transient memory per se. Rather, they appear to reflect impaired precision of operation of such systems, irrespective of the duration over which representations must be maintained. The severe deficits in processing precision, despite the relatively preserved maintenance of representation, may be relevant to pathophysiological models of schizophrenia.

Adult↗
PubMed1998

Impaired mismatch negativity (MMN) generation in schizophrenia as a function of stimulus deviance, probability, and interstimulus/interdeviant interval.

Schizophrenia is a severe mental disorder associated with disturbances in perception and cognition. Event-related potentials (ERP) provide a mechanism for evaluating potential mechanisms underlying neurophysiological dysfunction in schizophrenia. Mismatch negativity (MMN) is a short-duration auditory cognitive ERP component that indexes operation of the auditory sensory ('echoic') memory system. Prior studies have demonstrated impaired MMN generation in schizophrenia along with deficits in auditory sensory memory performance. MMN is elicited in an auditory oddball paradigm in which a sequence of repetitive standard tones is interrupted infrequently by a physically deviant ('oddball') stimulus. The present study evaluates MMN generation as a function of deviant stimulus probability, interstimulus interval, interdeviant interval and the degree of pitch separation between the standard and deviant stimuli. The major findings of the present study are first, that MMN amplitude is decreased in schizophrenia across a broad range of stimulus conditions, and second, that the degree of deficit in schizophrenia is largest under conditions when MMN is normally largest. The pattern of deficit observed in schizophrenia differs from the pattern observed in other conditions associated with MMN dysfunction, including Alzheimer's disease, stroke, and alcohol intoxication.

Acoustic Stimulation↗
PubMed1998

The role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes.

The study of excitatory amino acids (EAAs) has recently resulted in new and fundamental concepts in neuroscience. This progress has led to a growing awareness of the crucial role that brain EAAs systems play in a variety of physiological and pathological processes. The N-methyl-D-aspartate (NMDA) receptor, presently the most well understood subtype of EAAs receptors, has been implicated in crucial physiological processes such as synaptogenesis, learning and memory. Dysfunctions of NMDA receptors seem to play a crucial role in the neurobiology of disorders such as Parkinson's disease, Alzheimer's disease, epilepsy and ischemic stroke. This paper is a review of emerging data indicating that alterations of NMDA receptor function may be pivotal to the pathophysiology of four common psychiatric syndromes: schizophrenia, major depression, posttraumatic stress disorder, and alcoholism. Special emphasis is placed on the current state of development of pharmacological strategies aiming at the modulation of NMDA receptor-mediated neurotransmission in these disorders.

Alcoholism↗
PubMed1997

Electrophysiological indices of information processing in methylphenidate responders.

Event-related potential (ERP) studies report that the positive deflection following stimulus evaluation at 300 msec (P3) in hyperactive children is augmented by methylphenidate (MP). This study investigates P3 and preceding ERP components using an auditory oddball task in attention-deficit hyperactivity disorder (ADHD). Mismatch negativity, negativity at 100 and 200 msec, and positivity at 200 msec and 300 msec (P3) were obtained from 14 control and hyperkinetic children. ADHD children who responded to MP were tested on two separate days while receiving either MP or placebo. Controls were tested once. No differences were found between groups for ERP components preceding P3. P3 amplitude was significantly larger under MP than under placebo, but did not differ from controls. Under MP, differences in P3 amplitude unexpectedly occurred when no response was required. A P3 amplitude increase under MP and the unexpected P3 suggest that MP affects attention regulation.

Attention Deficit Disorder with Hyperactivity↗
PubMed1997

N-methyl-D-aspartate enhancement of phasic responses in primate neocortex.

In area 17 of the awake macaque, disinhibition by blockade of GABA(A) receptors results in a marked elevation in neuronal excitability, with a particular focus in the supragranular laminae. We examined the possibility that the excitatory supragranular response is N-methyl-D-aspartate (NMDA)-mediated. Laminar activity profiles consisting of flash-evoked field potential, current source density (CSD) and multiunit activity (MUA) measures were obtained during striate cortex penetrations using multicontact electrodes that incorporated single or double microinjection cannulae. Profiles were recorded before and at successive time points after bicuculline induction of disinhibition. Both the noncompetitive NMDA antagonist MK-801 and the competitive antagonist APV reversed bicuculline effects, producing a normal laminar activity profile. NMDA-mediated enhancement of excitatory responses in the supragranular laminae of neocortex is believed to play a role in normal signal processing, as well as in epileptic manifestations.

Animals↗
PubMed1997

Glycyldodecylamide, a phencyclidine behavioral antagonist, blocks cortical glycine uptake: implications for schizophrenia and substance abuse.

N-Methyl-D-aspartate (NMDA) antagonists induce psychotomimetic effects in humans that closely resemble negative and cognitive symptoms of schizophrenia. NMDA agonists, in contrast, may significantly ameliorate such symptoms. In rodents, phencyclidine (PCP) and other NMDA antagonists induce a hyperlocomotory syndrome that is reversed by NMDA agonists. The present study investigates the mechanism of action of glycyldodecylamide (GDA), a drug that is 80-fold more potent than glycine in reversing PCP-induced hyperactivity in rodents. At concentrations relevant to its behavioral actions, GDA significantly inhibits forebrain glycine uptake, indicating that glycine uptake inhibition may provide effective treatment for PCP psychosis and PCP psychosis-like symptoms of schizophrenia.

Animals↗
PubMed1997

Reversal of phencyclidine-induced hyperactivity by glycine and the glycine uptake inhibitor glycyldodecylamide.

Phencyclidine (PCP) induces a psychotic state that closely resembles schizophrenia. In preclinical studies, PCP has been shown to induce its unique behavioral effects by blocking excitatory neurotransmission mediated at the N-methyl-D-aspartate (NMDA) receptors, suggesting that agents which potentiate NMDA receptor-mediated neurotransmission might have clinically beneficial effects. The present study demonstrates that the NMDA co-agonist glycine inhibits rodent hyperactivity induced by PCP, but not amphetamine. Glycyldodecylamide, a compound that blocks neuronal glycine uptake and which may therefore increase intrasynaptic glycine levels, inhibits PCP-induced hyperactivity more potently than glycine. These results complement recent clinical studies with glycine and suggest that glycine-uptake inhibitors, as well as glycine, may be beneficial in the treatment of PCP-induced psychosis and schizophrenia.

Amphetamine↗
PubMed1997

Impaired precision, but normal retention, of auditory sensory ("echoic") memory information in schizophrenia.

Working memory is the type of memory that allows one to hold information in mind while working on a task or problem. The present study investigated attention-independent auditory sensory ("echoic") memory in 18 schizophrenic participants and 17 controls. Schizophrenic participants showed impaired delayed tone matching performance in comparison with controls. However, when groups were matched for performance at 1 s by varying the difficulty of the task across groups, schizophrenic participants showed normal retention of information as reflected in normal tone matching performance. These findings demonstrate that schizophrenic may be in the sensitivity of the system rather than the duration for which memory traces were retained.

Adult↗
PubMed1997

Serum neuroleptic levels during reduced dose fluphenazine decanoate maintenance therapy.

Forty-one remitted and chronically psychotic schizophrenic out-patients completed a two-year clinical trial during which they were assigned, on the basis of their clinically determined maintenance dosages, to one of two reduced, fixed-dose fluphenazine decanoate (FD) regimens: 35 mg/4 wks (19 patients) or 10 mg/4 wks (22 patients). Eighty-one percent of chronically psychotic patients, who represented 74% of the high dose group, relapsed, in comparison with only 38% of remitted patients (p < .001), who represented 86% of the low dose group. During this study serum neuroleptic levels were assessed, using the radioreceptor assay, before the administration of each FD injection and whenever a patient relapsed. Overall, 334 serum neuroleptic activity measurements were performed. Serum neuroleptic levels were detectable in all patients and were higher, although not significantly, in the 35 mg/4 wks group. The dichotomous clinical outcome of chronically psychotic and remitted patients occurred within the framework of essentially similar serum neuroleptic levels. These findings suggest that: 1) serum neuroleptic levels can be monitored during low dose FD treatment, 2) the poor maintenance therapy outcome of chronically psychotic patients cannot be accounted for by inadequate neuroleptic bioavailability, 3) a majority of remitted FD maintained patients retain their clinical response at serum neuroleptic levels lower than those initially attained at steady state.

Adult↗
PubMed1996

Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia.

Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are distributed in a modality-specific fashion throughout cortex. N-methyl-D-aspartate (NMDA) receptors play a crucial role in the initiation of long-term memory. Neurochemical mechanisms underlying the transient memory storage required for working memory, however, remain obscure. Auditory sensory memory, which refers to the ability of the brain to retain transient representations of the physical features (e.g., pitch) of simple auditory stimuli for periods of up to approximately 30 sec, represents one of the simplest components of the brain working memory system. Functioning of the auditory sensory memory system is indexed by the generation of a well-defined event-related potential, termed mismatch negativity (MMN). MMN can thus be used as an objective index of auditory sensory memory functioning and a probe for investigating underlying neurochemical mechanisms. Monkeys generate cortical activity in response to deviant stimuli that closely resembles human MMN. This study uses a combination of intracortical recording and pharmacological micromanipulations in awake monkeys to demonstrate that both competitive and noncompetitive NMDA antagonists block the generation of MMN without affecting prior obligatory activity in primary auditory cortex. These findings suggest that, on a neurophysiological level, MMN represents selective current flow through open, unblocked NMDA channels. Furthermore, they suggest a crucial role of cortical NMDA receptors in the assessment of stimulus familiarity/unfamiliarity, which is a key process underlying working memory performance.

Animals↗
PubMed1996

Premature disinhibition of P3 generation in schizophrenia.

P300 (P3) is a long-latency cognitive event-related potential (ERP) elicited by relevant target stimuli. P3 was recorded from 11 schizophrenics and 13 normal controls during a cued visual continuous performance task (CPT-AX). Cue-target sequences were presented at short and long interstimulus intervals (ISIs), in order to investigate working memory in schizophrenia. There was no significant between-group difference in P3 amplitude to validly or invalidly cued targets at short ISI. In contrast, P3 amplitude to invalidly cued targets at long ISI was significantly greater in schizophrenics than in controls, suggesting decreased ability to encode or maintain inhibitory representations of stimulus context. P3 amplitude is typically reduced in schizophrenic subjects in the auditory modality, and normal or reduced in the visual modality. This study, which demonstrates a paradoxical P3 increase to targets at long ISI, suggests that P3 impairment in schizophrenia cannot be attributed solely to structural deficits within P3-generator regions.

Adult↗
PubMed1996

A naturalistic outcome study of risperidone treatment among hospital patients.

Risperidone, an atypical antipsychotic, was introduced into clinical use in New York State facilities in April 1994. In this chart review study, records were reviewed for the first 63 patients started on risperidone at the Bronx Psychiatric Center during 1994. Sixty percent of patients treated with risperidone had a positive outcome, indicated by clinical improvement either at discharge or in the hospital. Twenty-two percent required termination of risperidone treatment within the initial three months. Risperidone appeared to be associated with favorable outcome among chronic state hospital patients, including those not discharged within the first three months of treatment.

Adult↗
PubMed1996

Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia.

BACKGROUND: It has been proposed that schizophrenia is associated with underactivity of brain glutamatergic neurotransmission, especially at the level of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Glycine potentiates NMDA receptor-mediated neurotransmission, indicating that it may serve as an effective therapeutic agent in the treatment of schizophrenia. METHOD: Eleven treatment-resistant patients with chronic schizophrenia completed a double-blind, placebo-controlled, six-week, randomly assigned, crossover treatment trial of 0.8 g/kg body weight/day of glycine, added to their prior antipsychotic treatment. RESULTS: Glycine was well tolerated, resulted in significantly increased serum glycine levels and induced a mean 36 (7%) reduction in negative symptoms (P < 0.0001). Significant improvements were also induced in depressive and cognitive symptoms. The greatest reduction in negative symptoms was registered in the patients who had the lowest baseline serum glycine levels. CONCLUSIONS: These results extend previous findings and suggest an additional approach to the pharmacotherapy of negative symptoms and cognitive deficits in schizophrenia.

Adult↗