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)

The psychoneuroendocrinology of schizophrenia derives from the presumption that neurotransmitter or receptor abnormalities in the limbic regions might extend to or influence the hypothalamus, which plays a role in the regulation of prolactin (PRL) secretion from the anterior pituitary gland. Since a GABA disturbance has been recently proposed in the pathogenesis of certain schizophrenic symptoms, and since a tuberoinfundibular-GABA (TI-GABA) system has been shown to modulate PRL secretion in humans, we tested the activity of this system both in controls and in chronic schizophrenic women. For this purpose the GABAergic drug sodium valproate (800 mg) was administered orally to 20 healthy women and 18 chronic schizophrenic women. Plasma PRL levels were measured before and after the drug administration. Sodium valproate decreased PRL concentrations only in the healthy women. Although the hypothesis of a GABA disturbance in schizophrenia at present is only speculative, these results might suggest a defect of the TI-GABA system in chronic schizophrenia.
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PMID:Failure of the GABAergic drug, sodium valproate, to reduce basal plasma prolactin secretion in chronic schizophrenia. 300 77

At the present time, the following summary statements can be made as to 24-hour changes in receptor binding. In all receptors studied in homogenates from whole rat forebrain (alpha 1, alpha 2, beta-adrenergic, muscarinic cholinergic, dopaminergic, 5HT-1, 5HT-2, adenosine, opiate, benzodiazepine, GABA, imipramine), significant variations over 24 hours have been documented. The receptor rhythms measured change in wave form, amplitude, and phase throughout the year, even though the animals have been kept on a defined and constant LD cycle. Whether these rhythms are truly seasonal requires further investigation. The rhythms are circadian: i.e. they persist in the absence of time cues, and the unimodal rhythms do not persist after lesion of the putative circadian pacemaker in the suprachiasmatic nuclei. The rhythms can be uni- or bimodal, and each brain region shows a particular pattern. The pattern can be different for the same ligand in different nuclei of a given brain region (e.g. hypothalamus). Nearly all studies of receptor rhythms have been carried out in rats; the results vary according to strain and even within the same strain from different breeding lines. Receptor rhythm characteristics are modified by age: e.g. the amplitude, phase, as well as the 24-hour mean of binding to a given ligand in a defined brain region. The changes in number of binding sites over 24 hours can be correlated with amine turnover, second messenger, or function of that brain region; however these relationships, although consistent within a region, do not hold for all regions. If gradual changes in CNS neurotransmitter receptor function are considered important in the pathogenesis of schizophrenia and affective disorders and the mode of action of psychopharmacological agents, then consideration of the short term rapid change over 24 hours is equally necessary. Chronic treatment with a number of psychoactive drugs known to induce up- or down-regulation of receptor number, also induces marked changes in circadian rhythm parameters of wave form, amplitude, phase and 24-hour mean. This is of methodological importance for single time-point studies, since the interpretation of the results will depend on time of day. Preliminary evidence supports the assumption that the significant variation in receptor binding throughout the day may underlie the well-known circadian rhythms of susceptibility to many CNS drugs. New findings of circadian rhythms in receptors on blood cells indicate the relevance of these changes also in human physiology.
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PMID:Circadian rhythms in mammalian neurotransmitter receptors. 303 6

The binding of the dopamine agonist ADTN and of ligands for the serotonin, muscarinic cholinergic, GABA, and benzodiazepine receptors was studied in 18 schizophrenic and 19 control brains. By contrast with the previously reported increase in binding of the dopamine antagonist spiperone, ADTN binding was not increased, and there was no consistent change in binding of ligands for receptors of substances other than dopamine. The findings suggest that the increase in dopamine receptors (assessed by spiperone binding) in schizophrenia is related to the disease process rather than to previous neuroleptic medication, and may be limited to the type of dopamine receptors that bind butyrophenones.
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PMID:Neurotransmitter receptors in brain in schizophrenia. 611 32

From the data presented and the clinical studies reviewed, it would appear that the tests presently used to forecast the clinical effects of GABA agonists are rather accurate in their predictability. Thus, these tests are positive for antiepileptic, antispastic and antidyskinetic potential; they are negative for schizophrenia and are at best equivocal for Huntington's disease. This is parallelled in a surprisingly close matter by the antidyskinetic, anticonvulsant and antispastic effects of at least one GABA agonist (progabide) in preliminary clinical testing. It is concluded the non-toxic GABA agonists will be useful in a variety of neurological disorders without precipatating incapacitating side effects.
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PMID:Neuropharmacological actions of GABA agonists: predictability for their clinical usefulness. 611 26

In rats, chronic (12 days) amphetamine administration (5 mg/kg, s.c.) resulted in more than 30% decrease of the glutamate content in the cerebrospinal fluid (CSF) and concomitant increase of glutamate levels in the frontal cortex, striatum and hippocampus. In contrast, chronic amphetamine had no effect on the GABA contents in these areas. The data are compatible with the interpretation that amphetamine induces an increase of dopaminergic function in these brain regions which results in an enhanced inhibition of glutamate release. It is hypothesized that diminished glutamate release accompanies the amphetamine psychosis as well as schizophrenia.
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PMID:Effects of chronic amphetamine treatment on the glutamate concentration in cerebrospinal fluid and brain: implications for a theory of schizophrenia. 611 45

Studies on the treatments for neuroleptic-induced tardive dyskinesia published in the literature are reviewed. The great number of different treatments and the controversial results of most studies show that there is as yet no specific and safe treatment for tardive dyskinesia. Suggestions for well-designed treatment studies are given: Placebo-controlled double-blind design, larger patient populations, clear diagnostic and standard observing and rating conditions using different assessment methods and videotapes, withdrawal of neuroleptics and antiparkinsonian drugs to discover reversible tardive dyskinesia. If this procedure is not feasible, neuroleptics and other drugs should be maintained at a stable dose level. Longer term studies of some months are necessary to study the prolonged efficacy of different drugs. The effect of dopamine-antagonists such as neuroleptics and of dopamine-depleting agents such as reserpine and oxypertine is of limited duration. Dopamine-agonists such as L-Dopa, bromocriptine and amantadine help only few patients and may even aggravate the symptoms of tardive dyskinesia. In some double-blind studies cholinergic drugs such as lecithin and deanol have improved tardive dyskinesia, but further controlled studies are needed. Anticholinergic drugs such as antiparkinsonian agents should not be prescribed because they may aggravate tardive dyskinesia. Some patients respond to GABA-ergic agents such as baclofen, sodium valproate and the benzodiazepines, but further studies are needed before the value of GABA-ergic agents in the treatment of tardive dyskinesia can be properly assessed. After withdrawal of neuroleptics the average of remission rates within a year is 20%-30%. Elderly patients are more likely to have persistent dyskinesias. A progressive stepwise diminution of the neuroleptic dose and of the antiparkinsonian agents is recommended. When a patient's psychosis is exacerbated after withdrawal of the neuroleptics and tardive dyskinesia is also present, small doses of thioridazine, clozapine or tiapride can be administered. If this practice is not successful cholinergic or GABA-ergic agents may be useful. Because no currently available therapeutic agents satisfies the criteria of safety, marked effectiveness and prolonged efficacy in the treatment of tardive dyskinesia, prevention becomes more important. Prolonged use of a neuroleptic medication requires careful evaluation of indications and risks. The doses of neuroleptic drugs during the maintenance treatment of schizophrenia should be as small as possible.
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PMID:[Therapeutic measures in tardive dyskinesia]. 613 57

Chronic (12 days) administration of sulpiride (50 mg/kg, i.p.) in rats resulted in a significant (12%) increase in the glutamate contents of cerebrospinal fluid. Sulpiride had no effect on the GABA content of the brain areas investigated (frontal cortex, striatum, hippocampus and substantia nigra). Sulpiride is a neuroleptic drug which is believed to block especially the non-adenylate cyclase dopaminergic receptors which are supposed to be inhibitory axoaxonic receptors on glutamatergic corticostriatal terminals. The results are compatible with the hypothesis that glutamatergic hypofunction might be the primary defect in schizophrenia rather than hyperactivity of the dopamine synapses.
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PMID:Cerebral glutamate, neuroleptic drugs and schizophrenia: increase of cerebrospinal fluid glutamate levels and decrease of striate body glutamate levels following sulpiride treatment in rats. 613 56

In addition to the dopamine hypothesis, a glutamate hypothesis has been recently discussed in the biochemical theories on the cause of schizophrenia. In schizophrenic patients less glutamic acid has been found in the cerebrospinal fluid. Glutamate is probably the most important excitatory transmitter of the mammalian forebrain. The liberation of glutamic acid in the striatum is inhibited by dopamine, more specifically by the D2 receptor, which is also though to be responsible for the antipsychotic effects of neuroleptic drugs. It seems possible that schizophrenia may be primarily caused by underfunction of glutamatergic corticostriatal and corticomesolimbic neurons rather than by overfunction of the dopaminergic system. The negative cognitive symptoms associated with schizophrenia would fit in with this hypothesis. The classical and the new atypical neuroleptic drugs show differential effects on glutamate and GABA in the brain tissue of the striatum and in the cerebrospinal fluid. Whereas sulpiride diminishes glutamate in the striatum and enhances glutamate in the cerebrospinal fluid, tiapride does not affect either of them. Correspondingly, tiapride does not show any antipsychotic effects. Haloperidol, on the other hand, enhances the GABA level in the striatum in a dose-related manner. These findings may perhaps prompt experimental research to find antipsychotic drugs with fewer side effects.
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PMID:[A biochemical theory of schizophrenia]. 615 Nov 20

GABA-ergic systems are involved in all the main functions of the brain. In most brain regions impairment of this system produces epileptic activity. GABA-mediated inhibitory function can be enhanced by drugs of at least seven different types. They act on the metabolism or synaptic release of GABA, or its reuptake into neurones of glia, or on various components of the GABA receptor complex (GABA recognition site, "benzodiazepine" receptor or chloride ionophore). Among such compounds, those which act most specifically and potently on GABA receptors remain primarily research tools. Among compounds in clinical use, valproate, benzodiazepines, and anticonvulsant barbiturates al enhance GABA-mediated inhibition. In the future, new inhibitors of GABA uptake, new GABA agonists and potent inhibitors of GABA-transaminase are likely to become available. Trials of drugs enhancing GABA-ergic function have been made in a wide variety of neurological disorders. In most forms of epilepsy a therapeutic effect is evident. Real benefit from GABA therapies has not been demonstrated in the principal disorders of movement (Huntington's chorea, Parkinson's disease, dystonias), except in so far as they have a myoclonic or paroxysmal component. Among psychiatric disorders the acute symptoms of schizophrenia are exacerbated by enhanced GABA-ergic function. Abstinence syndromes (alcohol, barbiturate or narcotic withdrawal) are ameliorated by drugs enhancing GABA-ergic function, and there is some evidence for a beneficial action in anxiety states and mania. Attempts to relate the molecular neurobiology of GABA with clinical pharmacology are of very recent origin. Improved understanding of the variety of GABA receptor mechanisms will provide the key to the more selective pharmacological manipulations that are required for therapeutic success.
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PMID:Pharmacology of GABA. 621 5

In two separate studies, we have obtained plasma levels of GABA in 134 psychiatric patients and 22 normal controls. Patients with a unipolar affective disorder had levels significantly lower than control (n = 58) as did patients with alcoholism (n = 10). Patients with a bipolar affective disorder had levels significantly higher than control when manic (n = 28) and also when euthymic on lithium prophylaxis (n = 17), but levels in the control range when depressed (n = 4). Patients with schizophrenia demonstrated a high degree of variability in their levels of plasma GABA but were not statistically different from control (n = 36). Patients with unipolar depression who received a dexamethasone suppression test had no correlation between nonsuppression of cortisol secretion and plasma levels of GABA. Diagnostic and research implication of plasma GABA in psychiatric illness are discussed.
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PMID:Plasma GABA levels in psychiatric illness. 623 45


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