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.

Chronic high-dose glycine nutrition: effects on rat brain cell morphology.

BACKGROUND: Facilitation of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission via administration of glycine site agonists of the NMDA receptor (e.g., glycine, D-serine), and glycine transport inhibitors may represent an innovative pharmacologic strategy in schizophrenia; however, given the potential involvement of NMDA receptors in the neurotoxicity of excitatory amino acids, possible neurotoxic effects of glycinergic compounds need to be explored. Furthermore, studying brain adaptations to chronic administration of glycine site agonists may provide insights into the therapeutic mechanisms of these drugs. METHODS: Adult rats were randomized to one of three nutritional regimens (no glycine supplementation, 1 g/kg/day, or 5 g/kg/day glycine supplementation) and to one of three treatment durations (1, 3, or 5 months). Serum glycine and serine levels at sacrifice and brain sections were examined using histologic markers of neurodegeneration (cresyl violet and silver impregnation staining) and immunohistochemical staining of glial fibrillary acidic protein, microtubule-associated protein, and neurofilament 200. To explore additional neural adaptations to high-dose glycine treatment, immunostaining was also performed for class B, N-type Ca(2+) channels. RESULTS: Serum glycine levels increased dose dependently during glycine nutrition, whereas serine levels were not changed. In hippocampal dentate gyrus, the percentage of hypertrophied astrocytes transiently increased at 1 month. At 3 and 5 months of glycine treatment, the density of class B, N-type Ca(2+) channels was reduced in parietal cortex and hippocampus. No evidence of neuronal or glial cell excitotoxic damage or degeneration was registered at either of the treatment intervals studied. CONCLUSIONS: These findings demonstrate for the first time that in vivo administration of high-dose glycine may induce brain morphological changes without causing neurotoxic effects. A reduction in density of class B, N-type Ca(2+) channels in specific brain regions may represent one general adaptation to long-term, high-dose glycine treatment.

Amelioration of negative symptoms in schizophrenia by glycine.

Phencyclidine induces a psychotomimetic state by blocking neurotransmission at N-methyl-D-aspartic acid (NMDA) receptors. In a double-blind, placebo-controlled fashion, 14 medicated patients with chronic schizophrenia were treated with glycine, a potentiator of NMDA-receptor-mediated neurotransmission. Significant improvement in negative symptoms occurred in the group given glycine but not in the group given placebo, suggesting that potentiation of NMDA-receptor-mediated neurotransmission may represent an effective treatment for neuroleptic-resistant negative symptoms in schizophrenia.

Trial of maintenance neuroleptic dose reduction in schizophrenic outpatients: two-year outcome.

BACKGROUND: An open trial was undertaken to assess the feasibility of reducing maintenance doses in a public clinical setting and to identify eventual predictors of outcome after dose reduction in schizophrenia. METHOD: Forty-one remitted and chronically psychotic schizophrenic outpatients were assigned, on the basis of their previously clinically determined maintenance dosages, to one of two reduced fluphenazine decanoate regimens: 35 mg/4 wk (19 patients) or 10 mg/4 wk (22 patients). Subsequently, patients were assessed, for a 2-year period, by means of the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, the Simpson-Angus Scale, and the Abnormal Involuntary Movement Scale. RESULTS: Chronically psychotic patients, who represented 74% of the high-dose group and only 14% of the low-dose group, had a significantly higher cumulative relapse rate (81%) than remitted patients (38%). For most remitted patients a dose of 10 mg of fluphenazine decanoate, injected every 4 weeks, was satisfactory. Both remitted and chronically psychotic patients displayed reductions in the severity of neuroleptic side effects. CONCLUSION: Maintenance dose reductions may be beneficial for many schizophrenic outpatients. Chronically psychotic and remitted patients maintained on lowered dosages differ significantly in the stability of their course of illness.

High dose glycine nutrition affects glial cell morphology in rat hippocampus and cerebellum.

Enhancement of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission by glycine (Gly) administration may represent a novel pharmacological strategy in schizophrenia. Given the involvement of NMDA receptors in plasticity and excitatory processes, the present study explores effects of Gly on brain cell morphology. Adult rats were randomized to receive, for 2 wk, no dietary supplementation or supplementation with 0.8 or 3.2 g/kg per day Gly. Glial cell morphology was examined using antibodies to glial fibrillary acidic protein (GFAP) and to microglial complement receptor 3 (CR3). Cresyl violet was used for general cellular staining. No evidence of neuronal or microglial pathology was found. Although astrocyte proliferation was not evident in Gly-treated rats, GFAP-like immunoreactivity was dose-dependently increased in the hippocampus (p<0.01), whereas in cerebellum, a dose dependent decrease in density of astocytic fibres was demonstrated (p<0.01). These findings demonstrate for the first time that in vivo administration of high dose Gly may induce brain morphology changes.

Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility.

RATIONALE: Tardive dyskinesia (TD) is a longterm adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3) ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extra-pyramidal effects profile of atypical antipsychotic drugs. OBJECTIVES: To examine the association of a functional polymorphism in the 5-HT2C receptor gene (HT2CR) with TD and the joint contribution of HT2CR and DRD3 to susceptibility. METHODS: Case control association analysis of allele and genotype frequencies among schizophrenia patients with (n=55) and without TD (n=60), matched for antipsychotic drug exposure and other relevant variables, and normal control subjects (n=97). Parametric analyses of the contribution of 5-HT2Cser and DRD3gly alleles to dyskinesia scores. RESULTS: We found a significant excess of 5-HT2Cser alleles in schizophrenia patients with TD (27.2%) compared to patients without TD (14.6%) and normal controls (14.2%; chi2=6.4, df 2, P=0.03) which was due to the female patients (chi2=8.6, df 2, P=0.01). Among the female TD patients there was an excess of cys-ser and ser-ser genotypes (chi2= 11.9, df 4, P=0.02). Analysis of covariance (ANCOVA), controlling for age at first antipsychotic treatment, revealed a significant effect of 5-HT2C genotype on orofacial dyskinesia (OFD) scores (F=3.47, df 2, P=.03). In a stepwise multiple regression analysis, 5-HT2C and DRD3 genotype (5-HT2Cser and DRD3gly allele carriage) respectively contributed 4.2% and 4.7% to the variance in OFD scores. CONCLUSIONS: These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.

The Patient Rejection Scale in an Israeli sample: correlations with relapse and physician's assessment.

The Patient Rejection Scale (PRS), which was developed to assess the feelings of rejection that relatives experience toward mental patients, was administered to a sample of 50 family members living with schizophrenic outpatients in Jerusalem, Israel. PRS response distribution was similar to that reported for a New York City sample. Total rejection scores were significantly correlated with a number of demographic variables and with the treating physician's assessment of the degree of rejection, hostility and criticism of the respective family members. Physician's rating of emotional over-involvement did not correlate with PRS scores. Both PRS and treating physician's ratings correlated significantly with course of illness parameters. The findings and their implications are discussed in the context of expressed emotion (EE) research.

Schizophrenia, chronic hospitalization and the 5-HT2C receptor gene.

Frequency of a polymorphism in the coding region of the 5-hydroxytryptamine2C (5-HT2C) receptor gene (HTR2C Xq24) was not significantly different in 122 unrelated Israeli schizophrenia patients compared with 180 control subjects matched for gender and ethnicity. However, proportion of time spent in hospital since the first admission was significantly greater in patients hemi- of homozygous for the 5-HT2Cser allele than in patients carrying other genotypes (p = 0.006). The 5-HT2Cser genotype conferred a 3.3-fold increased risk for lifetime hospitalization exceeding 10 years. Genetically determined variation in the 5-HT2C receptor may influence the clinical course and phenotypic expression of schizophrenia.

Treatment-resistant schizophrenia and staff rejection.

This study examined the relationship between characteristics of patients suffering from treatment-refractory schizophrenia and staff rejection and criticism. Subjects were 30 inpatients with treatment-resistant schizophrenia and the 29 staff members treating them. Measures included assessment of the patients' symptoms and aggression risk profile using the Positive and Negative Syndrome Scale (PANSS) and assessment of staff attitudes toward these patients using the Patient Rejection Scale (PRS). Nursing staff completed the Nurses' Observation Scale for Inpatient Evaluation (NOSIE). PRS ratings did not correlate with patients' demographic and treatment characteristics. Significant correlations existed, however, between increased staff rejection and higher scores for PANSS cognitive factor and NOSIE manifest psychosis factor. Negative symptoms, although preponderant in the patient sample, were not significant predictors of staff rejection on the PRS. Older nursing staff tended to view patients as more irritable and manifestly psychotic. These findings suggest that disorganized behavior and impaired cognition dysfunction areas are more likely to be associated with high levels of rejection among staff working with treatment-resistant schizophrenia patients. Incorporation of the relatively new concepts of cognitive dysfunction and treatment resistance in staff training programs and multidisciplinary team reviews may greatly benefit schizophrenia patients and the staff treating them.

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.

Risperidone-induced rabbit syndrome: an unusual movement disorder caused by an atypical antipsychotic.

Rabbit syndrome is a rare side effect of chronic neuroleptic administration characterized by rapid, fine, rhythmic movements of the mouth along a vertical axis. It gains its name from an unusual resemblance to the chewing and puckering motions of the rabbit. It is generally thought to be an extra-pyramidal side effect, in part due to its rapid response to anti-cholinergic medication. This is the first case report of risperidone, an atypical antipsychotic, inducing the syndrome. The theoretical implications for the classification of the syndrome along the spectrum of neuroleptic-induced movement disorders are discussed.

Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects.

The dopamine D4 receptor (DRD4) is a candidate gene in the search for a genetic etiology of schizophrenia and for pharmacogenetic factors in the response to antipsychotic treatment. Previous work has not found linkage or association of a polymorphism in exon 3 of this gene with diagnosis of schizophrenia or response to clozapine. In this study we examined this association in Israeli schizophrenic subjects treated with clozapine, compared to ethnically matched controls. Another polymorphism of this gene, in exon 1, was also studied. Both polymorphisms showed no association with schizophrenia or treatment response. A significant difference in allelic distribution of DRD/ exon 3 polymorphism was found between Ashkenazi and non-Ashkenazi control subjects.

Family expressed emotion: concepts, dilemmas and the Israeli perspective.

Family characteristics of high "expressed emotion" (EE) have been found to be predictive of relapse in schizophrenia and other psychiatric disorders. A causal relationship has been postulated between relapse and components of EE as assessed in the relatives with whom the patient has close social contact. Recently, conceptual and methodological aspects of the EE paradigm have become the focus of controversy. We present the dilemmas under debate and discuss the implications relevant to the study of EE in Israel.

Self-reported prescribing practices for schizophrenic patients among Israeli psychiatrists.

A "Schizophrenia Prescribing Practices Questionnaire" was developed and employed in order to obtain, directly from treating psychiatrists, information concerning their use of psychotropic medication in schizophrenia. The analysis of data furnished by 56 survey participants working in various institutions and treatment settings pointed to the following main findings: 1) the use of a wide range of antipsychotic (neuroleptic) drug dosages, 2) the use of high potency neuroleptics as the drugs of choice in all phases of treatment, 3) dissimilar dosing with the main high and low potency neuroleptics, 4) dissimilar haloperidol and chlorpromazine dosing in various types of treatment settings, 5) the use of combinations of neuroleptics and prophylaxis with antiparkinsonian drugs by more than 40% of the sample. The results of the survey are discussed in the context of recent research advances and current treatment recommendations.

Prescribing patterns of neuroactive drugs in 98 schizophrenic patients.

Ninety-eight schizophrenic outpatients receiving pharmacotherapy were surveyed on two census days, 18 months apart. From this study sample it was found that, as recently as 1987, 18% of the patients were prescribed three classes of neuroactive drugs--16% two antipsychotic drugs simultaneously. Of antipsychotics receivers, 44% were prescribed anticholinergics, 3% antidepressants, and 4% benzodiazepines. Between census days, a significant shift from use of oral antipsychotics to the depot form of administration occurred, while polypharmacy frequency remained unchanged. An analysis of the data will provide guidelines for rendering a more rational pharmacological treatment.

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.

Two-year trial of maintenance neuroleptic dose reduction in schizophrenic out-patients: predictors of relapse.

Low dose maintenance therapy has been proposed as a pharmacological strategy for reducing exposure to neuroleptic drugs in schizophrenia. However, reliable predictors of post-dose reduction relapse, which could guide clinicians in selecting patients suitable for this type of treatment, have not yet been determined. In this study, 41 schizophrenic out-patients were assigned, on the basis of their previously clinically determined dosages, to one of two reduced maintenance fluphenazine decanoate regimes (35 mg/4 wks. or 10 mg/4 wks.) and were assessed, subsequently, for a 2-year period. Demographic, clinical and treatment characteristics of relapsers (22 patients) and non-relapsers (18 patients) were compared using univariate and multivariate tests. Four parameters: age, course of illness, duration of illness and duration since last psychiatric hospitalization, suggested, in univariate tests, significant discrimination between relapsers and non-relapsers. Stepwise discriminant function analyses defined a highly significant function (p < .01) which included only 3 predictors of relapse. In order of importance, these predictors were: (1) a history of chronic psychosis (2) male sex, and (3) an illness of short duration. Parameters such as age, baseline rating scales scores, magnitude of dose reduction and baseline maintenance dose failed to improve the ability to discriminate between relapsers and non-relapsers. Implications of these findings for clinical practice are discussed.