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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Schizophrenia is a syndrome, undoubtedly with multiple etiologies, that variably exhibits several features including positive and negative symptoms, cognitive deficits, onset in young adulthood, and deterioration from the previous level of function. This review will examine the growing evidence that dysfunction of corticolimbic glutamatergic neurotransmission may contribute to or account for the manifestations of schizophrenia. Glutamatergic neurons represent the primary excitatory afferent and efferent systems innervating the cortex, limbic regions, and striatum. The postsynaptic actions of glutamate are mediated by a family of glutamate-gated ion channels that permit the influx of sodium and calcium, thereby depolarizing (exciting) neurons. One of these receptors, the N-methyl-D-aspartate (NMDA) receptor, is the site of action of psychotomimetics such as phencyclidine and related anesthetics, which can reproduce in normal individuals most of the symptomatic features of schizophrenia. An endogenous antagonist at the NMDA receptor, N-acetyl-aspartyl glutamate, appears to have enhanced activity in the frontal cortex and hippocampal formation in persons with this disorder. Glutamatergic dysfunction may be particularly relevant to those forms of schizophrenia in which negative symptoms, cognitive deficits, and deterioration are prominent features. In support of this inference, clinical studies have shown that drugs that enhance NMDA-receptor function reduce negative symptoms and cognitive deficits in persons with chronic schizophrenia who are receiving neuroleptics. Thus, dysfunction of glutamatergic neurotransmission represents an important organizational focus for research on the complex manifestations of schizophrenia.
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PMID:The glutamatergic dysfunction hypothesis for schizophrenia. 938 54

Synaptic pathology is central in the pathogenesis of several psychiatric disorders, for example in Alzheimer's disease (AD) and schizophrenia. Quantification of specific synaptic proteins has proved to be a useful method to estimate synapitc density in the brain. Using this approach, several synaptic proteins have been demonstrated to be altered in both AD and schizophrenia. Until recently, the analysis of synaptic pathology has been limited to postmortem tissue. In living subjects, these synaptic proteins may be studied through analysis of cerebrospinal fluid (CSF). In an earlier study performed by us, one synaptic vesicle specific protein, synaptotagmin, was detected in CSF for the first time using a procedure based on affinity chromatography, reversed-phase chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and chemiluminescence immunoblotting. However, other synaptic proteins were not detectable with this procedure. Therefore, we have developed a procedure including precipitation of CSF proteins with trichloroacetic acid, followed by liquid-phase isoelectric focusing using the Rotofor Cell, and finally analysis of Rotofor fractions by Western blotting for identification of synaptic proteins in CSF. Five synaptic proteins, rab3a, synaptotagmin, growth-associated protein (GAP-43), synaptosomal-associated protein (SNAP-25) and neurogranin, have been demonstrated in CSF using this method. The major advantage of liquid-phase isoelectric focusing (IEF) using the Rotofor cell is that it provides synaptic proteins from CSF in sufficient quantities for identification. This method may also be suitable for identification of other types of trace amounts of brain-specific proteins in CSF. These results demonstrate that several synaptic proteins can be identified and measured in CSF to study synaptic function and pathology in degenerative disorders.
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PMID:Identification of synaptic vesicle, pre- and postsynaptic proteins in human cerebrospinal fluid using liquid-phase isoelectric focusing. 1021 48

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.
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PMID:Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. 1036 50

Previous investigations have found that increasing circulating glucose availability can increase memory performance in rodents, healthy humans, and individuals with dementia of the Alzheimer's type. In this study, patients with schizophrenia, healthy control subjects, and controls with bipolar affective disorder were tested using double-blind treatment with either 50 g anhydrous dextrose plus 4 mg sodium saccharin (for "taste") or 23.7 mg saccharin alone, followed by cognitive testing on a complex battery. At this glucose dose, verbal memory performance on a paragraph recall task was increased during the glucose condition relative to the saccharin condition in the patients with schizophrenia; this effect was not detected in either the psychiatric or normal controls. The results provide preliminary support for the hypothesis that memory performance can be improved in patients with schizophrenia by increasing circulating glucose availability and suggest the importance of further evaluation of therapeutic manipulations of glucose availability.
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PMID:Glucose-induced increase in memory performance in patients with schizophrenia. 1041 34

This review covers some recent findings of the electrophysiological mechanisms through which mesocortical dopamine modulates prefrontal cortical neurons. Dopamine has been shown to modulate several ionic conductances located along the soma-dendritic axis of prefrontal cortical pyramidal neurons. These ionic currents include high-voltage-activated calcium currents and slowly inactivating Na+ and K+ currents. They contribute actively in processing functionally segregated inputs during synaptic integration. In addition, dopamine mainly depolarizes the fast-spiking subtype of local GABAergic interneurons that connect the pyramidal neurons. This latter action can indirectly control pyramidal cell excitability. These electrophysiological data indicate that the actions of dopamine are neither "excitatory" nor "inhibitory" in pyramidal prefrontal cortex neurons. Rather, the actions of dopamine are dependent on somadendritic loci, timing of the arrival of synaptic inputs, strength of synaptic inputs, as well as the membrane potential range at which the PFC neuron is operating at a given moment. Based on available electrophysiological findings, a neuronal model of the pathophysiology of schizophrenia is presented. This model proposes that episodic hypo- and hyperactivity of the PFC and the associated dysfunctional mesocortical dopamine system (and their interconnected brain regions) may coexist in the same schizophrenic patient in the course of the illness. We hypothesize that the dysfunctional mesocortical dopamine input to the PFC may lead to abnormal modulation of ionic channels distributed in the dendritic-somatic compartments of PFC pyramidal neurons that project to the ventral tegmental area and/or nucleus accumbens. In some schizophrenics, a reduction of mesocortical dopamine to below optimal levels and/or a loss of local GABAergic inputs may result in a dysfunctional integration of extrinsic associative inputs by Ca2+ channel activity in the distal dendrites of PFC pyramidal neurons. This may account for the patients' distractibility caused by their inability to focus only on relevant external inputs. In contrast, in acute stress or psychotic episodes, an associated abnormal elevation of mesocortical dopamine transmission may greatly influence distal dendritic Ca2+ channel-mediated signal-processing mechanisms. This can enhance possible reverberative activity between adjacent interconnected pyramidal neurons via the effects of dopamine on the slowly inactivating Na+, K+, and soma-dendritic Ca2+ currents. The effects of high levels of PFC dopamine in this case may contribute to behavioral perseveration and stereotypy so that the patients are unable to use new external cues to modify ongoing behaviors.
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PMID:Developing a neuronal model for the pathophysiology of schizophrenia based on the nature of electrophysiological actions of dopamine in the prefrontal cortex. 1043 66

1. Increased water intake and output is more common among psychiatric patients, especially those with schizophrenia, than in the general population. Animal studies suggest that polydipsia and polyuria derive, in part, from dopamine dysregulation. Stimulated by these observations this study sought to elucidate relationships among water homeostasis, monoamine metabolism, and electrolyte excretion in schizophrenic patients with and without paranoid hallucinatory symptoms (PH vs. NP), thought to reflect hyper- and hypo-dopaminergic states respectively, and to compare these with those shown by patients with obsessive compulsive disorder (OCD). 2. 24 hr-urine samples for electrolyte, monoamine and metabolite measures were taken from 14 schizophrenic patients with PH symptoms, 13 with predominantly nonparanoid (NP) symptoms, 11 OCD patients and 27 healthy controls (matched for age, weight and creatinine production). Water intake and serum electrolytes was sampled during psychological testing. 3. PH patients drank 2-3 times more than the others in a 3-4 hr test, yet 24 hr-urinary volumes were 75% larger in both PH and NP patients than in the two comparison groups. 4. Daily potassium excretion was a bit higher in PH patients, but concentrations of sodium, potassium and phosphate tended to be lower in PH and NP patients than in the others. 5. Positive associations of electrolyte with homovanillic acid excretion were consistent across groups and not directly related to medication. But associations of electrolyte excretion with noradrenergic activity in controls were absent in psychotic patients and associations with serotonin in OCD patients were absent in the other groups. 6. Increased water intake and output in PH patients along with the disturbed association with noradrenergic metabolism are consistent with altered autonomic activity in these patients. 7. The independence of measures of water homeostasis from dopaminergic medication indicates that the associations in clinically responding PH patients of polydipsia with DA function (decreased DA levels) may be pertinent to this subgroup but not to schizophrenia in general.
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PMID:Subclinical polydipsia and polyuria in young patients with schizophrenia or obsessive-compulsive disorder vs normal controls. 1063 61

Prescribing patterns for a group of outpatients with schizophrenia were surveyed for changes after the initiation of clozapine. Data were drawn from computerized pharmacy records, direct case record reviews, and interviews with the attending psychiatrists. The number of patients with two or more psychotropic drugs decreased by 31 percent after the initiation of clozapine, and a trend toward the use of clozapine without additional neuroleptics was detected. Decreases occurred in the use of anticholinergic agents, carbamazepine, and benzodiazepines, but selective serotonin reuptake inhibitors and sodium valproate were more likely to be prescribed concomitantly with clozapine.
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PMID:Effect of clozapine on polypharmacy. 1065 14

Olanzapine is a novel antipsychotic effective in reducing positive and negative symptoms of schizophrenia and with a safe side-effect profile. Premarketing trials, however, included only a few elderly patients. Further data are needed regarding the effects of olanzapine in the elderly and those with comorbid medical illness. In this pilot study, 11 hospitalized patients (age range 60-85 years) who manifested symptoms of psychosis related to schizophrenia and schizoaffective disorders were treated with olanzapine (dose range, 5-20 mg/day). Efficacy and safety were assessed by the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale (CGI), Extrapyramidal Symptom Rating Scale (ESRS), Mini-Mental State Examination (MMSE), Calgary Depression Scale For Schizophrenia (CDSS), EKG, physical examination, and various laboratory tests. Seven patients responded to treatment and all of them showed improvement in both positive and negative symptoms, with greater reduction in positive symptoms. Treatment was discontinued in 2 patients whose symptoms showed no improvement or worsened. The CGI showed significant improvement in 9 patients, remained the same in 1, and worsened in 1 patient. ESRS showed significant reduction from baseline to final visit. Of the 10 patients who cooperated for MMSE, 9 had improved scores. The CDSS showed significant reduction in scores from baseline to final visit. No significant changes were noted in laboratory tests, prolactin levels, EKG, and physical examination. Concomitant administration of lorazepam, carbamazepine, divalproex sodium, and lithium carbonate caused no adverse consequences. The reduction of positive and negative symptoms, lack of significant extrapyramidal symptoms and other side effects, and lack of any significant drug interaction suggest that olanzapine may be a safe and effective antipsychotic medication in the elderly.
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PMID:Efficacy and tolerability of olanzapine in elderly patients with psychotic disorders: a prospective study. 1079 21

We report an unusual case of thrombocytopenia associated with neuroleptic malignant syndrome (NMS). A 31-year-old Black male with a history of hypertension, partial seizures, and schizophrenia developed acute rigidity closely followed by severe hyperpyrexia (temperature 102 degree F), tachypnea, and tachycardia. His home medications at the time of presentation included propanolol 10 mg tid, haloperidol 10 mg bid, sodium valproate 500 mg bid, benztropine 1 mg bid, and haloperidol decanoate 100 mg i.m. every 3 weeks, from another psychiatric facility. Despite vigorous therapy for the hyperthermia, he rapidly developed significant hypoxia requiring mechanical ventilation. A diagnosis of neuroleptic malignant syndrome was made and the patient continued to receive aggressive supportive care. On hospital day 2 his platelet count dropped to 47,000/microl and bottomed out at 36,000/microl by day 3 with other blood cell counts remaining within normal limits. Over the next few days he showed rapid clinical improvement with normalization of his blood chemistries and he was discharged home after 5 days of hospitalization in good condition.
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PMID:Neuroleptic malignant syndrome and severe thrombocytopenia: case report and literature review. 1079 26

Experimental and clinical data suggest that GABA-ergic drugs such as valproate may have a potential role in the treatment of schizophrenia. The authors designed a 21-day prospective, double-blind, randomized, placebo-controlled pilot study of divalproex sodium as add-on treatment to haloperidol in 12 hospitalized patients with acute exacerbations of chronic schizophrenia. All patients received haloperidol 10 mg/day for 3 days and 15 mg/day for the remaining 18 days. In addition, five patients were randomly assigned to receive divalproex augmentation and seven to receive placebo. The divalproex dose was adjusted to a target serum concentration of 75 microg/mL for 2 weeks; placebo replaced divalproex during the third and last weeks to determine any carryover effect. Psychiatric rating scales were administered at baseline and on days 7, 14, and 21. Although the placebo group improved with haloperidol treatment, the divalproex group demonstrated greater improvement. On day 21, the divalproex group had greater improvement from baseline on the Clinical Global Impression Scale (p < or = 0.04), Brief Psychiatric Rating Scale (p < or = 0.13), and Schedule for Assessment of Negative Symptoms scores (p < or = 0.007). After divalproex withdrawal on day 15, a carryover effect was observed during week 3. The authors concluded that the addition of divalproex sodium to standard antipsychotic drugs may prove effective in relieving the symptoms of acute schizophrenia. Future studies may benefit from the design of this pilot study. However, it is premature to apply this augmentation strategy in the clinical setting just yet because of the small sample size and the likely heterogeneity of the disorder.
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PMID:Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. 1083 Oct 24


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