Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disordered water balance, or polydipsia, is an underassessed and underreported phenomenon present in the severely psychiatrically disabled population. Prevalence rates for polydipsia range from 6.2 to 20%. We followed up five male patients (mean age 43) with chronic schizophrenia who met the Kane criteria for being treatment nonresponders and who, in addition, had marked polydipsia. Three patients had previously received medical care for hyponatremia and had to be placed on fluid restriction when admitted to the hospital. All patients exhibited polydipsia despite high doses of typical antipsychotic drugs. Each patient was treated openly with clozapine (range 450-800 mg/day) for at least 6 months. In each case, there was a decline in the Brief Psychiatric Rating Scale score (preclozapine mean, 63; postclozapine mean, 46), and a marked reduction in fluid-seeking behavior. All fluid restrictions could be lifted, and the patients were discharged from the hospital. During a mean follow-up period of 17 months, during which patients were evaluated weekly, polydipsic behavior that required intervention had not been noted. We conclude that clozapine may be a highly effective treatment for polydipsia in patients with treatment-refractory schizophrenia. Future studies may aim to delineate neurobiologic mechanisms.
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PMID:Clozapine reduces water-drinking behavior in schizophrenic patients with polydipsia. 883 10

Fluid-electrolyte balance is regulated within a narrow range and disturbances in this system are unusual in animals and humans. Studies from the preneuroleptic era to date suggest that up to 25 percent of patients with schizophrenia have polydipsia, suggesting that it is related to the pathophysiology of the psychoses. Polydipsia and the related phenomenon of hyponatremia cause considerable mortality and morbidity. Prevalence studies are limited by imprecise measures available at present. The treatment was limiting water intake when patients reached critical levels of water retention, which however did not improve polydipsia. Recent case reports and open studies have shown that clozapine improves both polydipsia and water retention. The response occurs at low doses and is not related to improvement in psychosis. This may not be applicable to all patients and better understanding of the pathophysiology of polydipsia-hyponatremia would lead to more empirically derived treatments.
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PMID:Problems and progress in the diagnosis and treatment of polydipsia and hyponatremia. 887 96

Latent inhibition (LI) refers to retarded conditioning to a stimulus that has been repeatedly presented without reinforcement. LI is impaired in schizophrenia patients and in rats treated with amphetamine. Neuroleptic drugs produce two effects in this test paradigm: antagonism of amphetamine-induced disruption of LI, and enhancement of LI when administered on their own. The present experiments tested the effects of the atypical neuroleptic, clozapine, on LI. The experiments used a conditioned emotional response procedure in rats licking for water, consisting of three stages: preexposure, in which the to-be-conditioned stimulus (tone) was repeatedly presented without reinforcement; conditioning, in which the preexposed stimulus was paired with reinforcement (foot shock); and test, in which LI was indexed by animals' degree of suppression of licking during tone presentation. In experiments 1 and 2, the effects of 5.0 and 10.0 mg/kg clozapine on LI were assessed following 20 or 10 tone preexposures, respectively. Experiments 3 and 4 used 40 preexposures and investigated antagonism of amphetamine-induced disruption of LI by 5.0 and 10.0 mg/kg clozapine, respectively. The results demonstrated that clozapine possesses a neuroleptic profile in the LI model, namely, it facilitates the development of LI and antagonizes amphetamine-induced disruption of LI.
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PMID:The latent inhibition model of schizophrenia: further validation using the atypical neuroleptic, clozapine. 889 69

Polydipsia can be defined as an impulsive behavior leading to absorption of large amounts of water (4 to 20 litres a day), without any underlying organic disease. Its prevalence in a population of chronic psychiatric patients can be as high as 6 to 17%. Schizophrenia represents 80% of cases reported. Some patients with polydipsia may develop hyponatremia, leading to a PIP syndrome (Polydipsia intermittent hyponatremia and psychosis). Hyponatremia or water intoxication appears when three conditions are present: an abnormal regulation of thirst, an inappropriate ADH secretion and/or an excessive renal sensitivity to ADH, with an increased sensitivity of the central nervous system to hyponatremia. The clinician must first identify patients at risk to develop water intoxication and start treatment before any severe physical complication occurs. Pharmacological treatments aiming at an increase of renal free-water excretion--do not show a constant efficacy in the correction of hyponatremia, they have no action on polydipsia. The new atypical neuroleptics such as clozapine and risperidone seem to open new perspectives in the treatment of polydipsia. Controlled studies should be performed in this field.
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PMID:["Polydipsia, intermittent hyponatremia and psychoses" syndrome: a diagnosis and therapeutic management of a case]. 892 56

The two most important afferent projections to the striatum contain glutamate and dopamine, respectively. Excitotoxic damage resulting from excessive stimulation of the N-methyl-D-aspartate subtype of glutamate receptor has been implicated in pathophysiology of ischaemic stroke, hypoglycaemic brain damage and Huntington's disease. We studied the ability of the dopamine system to modify the anatomical, neurochemical and behavioural consequences of glutamatergic toxicity in the striatum. In a first set of experiments, the specific N-methyl-D-aspartate receptor agonist quinolinate was injected unilaterally into the striatum of rats pretreated with one of (i) intraperitoneal (i.p.) saline (controls); (ii) i.p. haloperidol, a D2 dopamine receptor agonist; or (iii) 6-hydroxydopamine lesion of the ipsilateral nigrostriatal tract. Quinolinate-induced striatal damage, as assessed by morphometric and neurochemical criteria, was significantly attenuated in the animals with 6-hydroxydopamine lesions and in those pretreated with haloperidol, compared with saline-pretreated controls. There were no significant differences between the 6-OHDA and haloperidol groups. In a second set of experiments, animals received (i) bilateral intrastriatal quinolinate plus perioperative i.p. saline; (ii) bilateral intrastriatal quinolinate plus i.p. haloperidol; or (iii) bilateral intrastriatal saline. Again, the quinolinate-lesioned animals treated with perioperative haloperidol had significantly less striatal damage than the bilateral quinolinate rats. Behavioural assessment in the Morris Water Maze showed the bilateral quinolinate+haloperidol group to be significantly less impaired on a spatial acquisition task than the bilateral quinolinate animals. Measures of spontaneous daytime motor activity showed significant differences in average speed and rest time between the bilateral quinolinate+haloperidol rats and the bilateral quinolinate group. The performance of the bilateral quinolinate+haloperidol group was not significantly different from that of controls on any of the behavioural tasks. These results indicate an important role for D2 dopamine receptor-mediated mechanisms in striatal excitotoxicity. Since the excitotoxic process involves the same fundamental signalling mechanism that is involved in normal glutamatergic transmission, these findings imply an ability of D2 receptor blockade to modify glutamate signalling in the striatum. These results may have implications for treatment strategies in ischaemic stroke, hypoglycaemic brain damage and schizophrenia.
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PMID:Dopamine-glutamate interactions in the striatum: behaviourally relevant modification of excitotoxicity by dopamine receptor-mediated mechanisms. 893 42

Changes in regional cerebral blood flow (rCBF), associated with performance of an auditory verbal supraspan memory task, were studied in eight remitted DSM-III-R schizophrenic patients and eight pair-wise matched normal controls. Four positron emission tomography (PET) scans, using the [15O]-H2O technique, were acquired: two while subjects fixated a cross hair and two while performing a verbal free-recall supraspan memory task. Task performance showed typical patterns of recency and primacy effects in both groups; however, patients performed more poorly than controls on the primary (working) memory aspect of the task. Regions showing rCBF changes overlapped in both groups and were similar to those seen in previous studies of normals; however, patients had smaller increases in rCBF than controls in frontal and superior temporal cortical regions bilaterally. Our results suggest that remitted patients with schizophrenia demonstrate impairments of capacity-limited information processing, which may be related to metabolic dysfunction within a distributed network of brain structures, including the prefrontal and temporal cortical regions; however, dysfunction limited to the frontal cortex cannot be ruled out by the results of this experiment.
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PMID:PET brain mapping study of auditory verbal supraspan memory versus visual fixation in schizophrenia. 898 93

Amisulpride, a benzamide derivative, is an antipsychotic drug with a pharmacological profile distinct from that of classical neuroleptics such as haloperidol and from that of another benzamide, remoxipride. In mice, amisulpride antagonized hypothermia induced by apomorphine, quinpirole or (+/-) 7-hydroxy-2-(di-n-propylamino)-tetralin, an effect involving D2/D3 receptors, at similar doses (ED50 approximately 2 mg/kg i.p.), which were much lower than doses that blocked apomorphine-induced climbing, an effect involving postsynaptic D2 and D1 receptor activation (ED50 = 21 mg/kg i.p.). Much higher doses (ED50 = 54 mg/kg i.p.) of amisulpride were needed to block grooming behavior observed after a short period in water, a D1 receptor-mediated behavior. In rats, amisulpride preferentially inhibited effects produced by low doses of apomorphine (hypomotility and yawning), related to stimulation of presynaptic D2/D3 dopamine autoreceptors (ED50 = 0.3 and 0.19 mg/kg i.p.). By contrast, amisulpride antagonized apomorphine-induced hypermotility, a postsynaptic dopamine receptor-mediated effect, at a much higher dose (ED50 = 30 mg/kg i.p.). Amisulpride (100 mg/kg i.p.) only partially inhibited apomorphine-induced stereotypies (gnawing) and had no effect on stereotypies induced by d-amphetamine. However, d-amphetamine-induced hyperactivity was antagonized by doses of amisulpride as low as 3 mg/kg i.p., which may indicate selectivity of this drug for limbic dopaminergic mechanisms. In addition, in contrast to haloperidol or remoxipride, which produced catalepsy at doses 2 or 3 times higher than those that antagonized stereotypies induced by apomorphine, amisulpride did not induce catalepsy up to a dose of 100 mg/kg i.p., which occupies 80% of striatal D2 receptors. This pharmacological profile of amisulpride, characterized by a preferential blockade of effects involving presynaptic mechanisms and limbic structures, may explain the clinical efficacy of this drug against both negative and positive symptoms of schizophrenia and its low propensity to produce extrapyramidal side effects.
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PMID:Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. 899 84

In the present study we attempted to further define the time course and regional specificity of lead (Pb)-induced changes in the NMDA receptor complex and the influence of dopaminergic system modulations on these changes. Autoradiographic measurements of alterations in MK-801 binding, as evaluated under four different activation conditions (none, spermidine, glycine, or maximal activation), were performed in medial frontal cortex, dorsal striatum, and nucleus accumbens of male rats after 2 weeks or 8 months of chronic postweaning (from 21 days of age on) exposure to 0, 50, or 150 ppm Pb acetate in drinking water. The 8-month groups also received chronic intermittent intraperitoneal injections of saline, or of the dopamine (DA) agonist apomorphine or the D1 agonist SKF-82958 2-3 times per week beginning at 60 days of age. Two weeks of 50 ppm Pb exposure resulted in small but significant increases in MK-801 binding under conditions of glycine or spermidine activation, whereas decreases were observed in response to 150 ppm under conditions of no or maximal activation in all regions. After 8 months of Pb, concentration-dependent decreases in MK-801 binding were observed across regions under all activation conditions. These effects were noted at blood Pb concentrations averaging as low as 16 microg/dl. Pb-induced decreases in MK-801 binding were either partially or fully reversed by chronic intermittent treatment with the DA agonist apomorphine but not by the D1 agonist SKF-82958, implicating D2-based mechanisms in this reversal. Combined findings from this and previous studies based on this exposure protocol indicate a Pb-induced pattern of widespread hypoglutamatergic function accompanied by increased DA function in mesolimbic systems, a pattern of changes reminiscent of those proposed to underlie schizophrenia. Such findings suggest that Pb exposure, even at current environmental levels, could be a risk factor for behavioral and/or neurological disturbances arising from imbalances of glutamate/dopamine function in mesocorticolimbic systems.
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PMID:Time course and regional basis of Pb-induced changes in MK-801 binding: reversal by chronic treatment with the dopamine agonist apomorphine but not the D1 agonist SKF-82958. 910 27

Latent inhibition (LI) is a behavioural paradigm in which repeated nonreinforced preexposure to a stimulus inhibits the formation of subsequent associations to that stimulus. LI is believed to reflect learning to ignore irrelevant stimuli. Disrupted LI has been suggested as an animal model for the attentional deficits observed in schizophrenia. Remoxipride, a selective dopamine D, antagonist, is an effective antipsychotic with an atypical clinical profile. We investigated the effects of remoxipride (1.0, 5.0, and 10.0 mg/kg) and haloperidol (0.1 mg/kg) administration on LI in rats. A three-stage conditioned emotional response procedure was employed: a) preexposure: preexposed rats received 10 presentations of a flashing light stimulus without reinforcement, and nonpreexposed rats received no exposure: b) conditioning; the preexposed stimulus was paired with a foot shock over a number of trials: c) test: LI was expressed by the extent of suppression of water licking during flashing light presentation. Animals receiving 0.1 mg/kg of haloperidol or 1.0 or 5.0 mg/kg (but not 10.0 mg/kg) of remoxipride treated the preexposed stimulus as irrelevant after a low number of preexposed. These results illustrate that the LI model is equally sensitive to typical and atypical antipsychotics and reemphasises its utility as a test model for detecting the antipsychotic potential of novel drugs.
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PMID:Enhancement of latent inhibition in the rat by the atypical antipsychotic agent remoxipride. 913 Mar 9

Animal studies have suggested the involvement of the adrenergic system in drinking behavior. The present study investigated the involvement of the alpha2-adrenergic system in the polydipsia of patients with chronic schizophrenia by use of an alpha2 agonist and an antagonist. Four patients with schizophrenic disorders accompanied by intermittent hyponatremia and polydipsia were the subjects of, and completed, this study. Drinking behavior was assessed by calculating the percent of maximum weight gain [PMWG: (maximum diurnal weight - standard weight) x 100/standard weight]. Standard weight was defined as body weight after 8 h of water restriction. Clonidine (75, 150, and 225 mg/day) increased the PMWG in a dose-dependent manner in the four subjects. In contrast, in three of the subjects, mianserin (30, 60, and 90 mg/day) decreased PMWG, and the severe polydipsia disappeared almost completely. These findings indicate clearly that the alpha2-adrenergic system is involved in the drinking behavior of schizophrenic patients. Mianserin appears to be clinically useful in treating such patients with polydipsia.
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PMID:Involvement of the alpha2-adrenergic system in polydipsia in schizophrenic patients: a pilot study. 916 Aug 55


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