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)

Monoamine neurotransmitter systems are widely thought to be involved in the pathophysiology of affective disorders and schizophrenia and the mechanism of action of antidepressant and antipsychotic drugs. Previous clinical studies have focused on individual monoamine function in isolation, even though a large number of preclinical studies have demonstrated that monoamine neurotransmitter systems interact with one another. In the present paper, preclinical data on monoamine neurotransmitter interactions are reviewed, and two methods for examining monoamine neurotransmitter system interactions in clinical data are presented. One of the best replicated findings in biological psychiatry is that monoamine metabolites in CSF correlate with one another. The degree of correlation may be in part a measure of the degree of interaction between the parent monoamine neurotransmitter systems. Another approach to studying interactions is the use of HVA/5HIAA and HVA/MHPG ratios as an index of interactions between 5HT-DA and NE-DA. When these methods are applied in schizophrenia, patients are found to have decreased monoamine metabolite correlations compared to normal controls. Metabolite correlations increase significantly after antipsychotic treatment, and the HVA/5HIAA and HVA/MPHG ratios also increase, suggesting that neuroleptics may act in part by strengthening interactions between monoamines. BPRS ratings are negatively correlated with HVA/5HIAA and HVA/MHPG so that patients with higher ratios have fewer symptoms, particularly after treatment. These results provide direct experimental support for hypotheses suggesting that interactions between monoamine neurotransmitters are important in schizophrenia. Some of the effects of the atypical neuroleptic, clozapine, on metabolite correlations and ratios are also discussed.
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PMID:Clinical investigation of monoamine neurotransmitter interactions. 783 44

The effect of the selective serotonin-2 antagonist ritanserin was investigated in an open study of patients with schizophrenia. The patients were in an acute psychotic state considered to require neuroleptic medication. No neuroleptic drug was allowed during the study or during the last month preceeding the study. Oxazepam or nitrazepam were allowed for sedation or sleep inducement. Safety, tolerability, potential antipsychotic effect, and drug effects on monoamine metabolites in serum and CSF and prolactin in serum were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography. Ten male patients (mean age 32.4) fulfilling DSM-III-R criteria for schizophrenia were included in the study. Nine of these patients completed 4 weeks' treatment with ritanserin 10 mg b.i.d. The clinical effect was evaluated by means of CPRS and SANS and significant improvement was seen after 4 weeks' treatment both in positive and negative symptoms. Ritanserin was well tolerated and no extrapyramidal symptoms or akathisia were seen. Concentrations of monoamine metabolites and prolactin did not change during treatment. Ritanserin did not occupy D2-dopamine receptors. Thus, no indications of any D2-dopamine-antagonistic activity were obtained. All patients had expected ritanserin levels in plasma during the whole study. This first study of a selective serotonin-2 antagonist in the treatment of acute schizophrenic patients demonstrated significant clinical effects. However, the open design of the study does not allow us to conclude with any certainty that the patients' improvement was due to a specific blockade of serotonin-2 receptors or unspecific factors, although a direct D2-dopamine blockade could be ruled out.
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PMID:An open clinical and biochemical study of ritanserin in acute patients with schizophrenia. 784 5

Negative symptoms (and cognitive impairments) in schizophrenia are a correlate of early onset and poor outcome. It is plausible that they are related to an arrest of brain development, for which there is now considerable evidence, but the precise relationship is elusive. In one post-mortem study negative symptoms were related to a reduction in brain length and in an MRI study to an asymmetry of sulcal CSF. It is proposed that the phenomena of psychosis (including negative symptoms) can be understood as part of the diversity of human personality structure generated by a process of sexual selection acting on a sexual dimorphism for cerebral asymmetry.
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PMID:Brain changes and negative symptoms in schizophrenia. 787 Nov 16

CSF diazepam-binding inhibitor-like immunoreactivity (DBI-LI) and polysomnography were studied in 28 drug-free male schizophrenic (DSM-III-R) patients. They underwent a three-night polysomnography evaluation and a lumbar puncture. CSF DBI-LI correlated positively with REM latency, the REM latency/2d nonREM period ratio and stage-4% sleep, and negatively with stage-1% sleep. CSF DBI-LI did not correlate significantly with duration of sleep or sleep latency. CSF DBI-LI during haloperidol treatment did not correlate significantly with sleep EEG measures. The results of this first study of the relationship between endogenous DBI and sleep in humans suggest that physiological effects of DBI other than interactions with the BZD/GABAA receptor complex may explain its positive effects on sleep. However, the absence of similar sleep data in normal subjects precludes us from establishing a specific relationship between DBI and sleep in schizophrenia.
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PMID:CSF levels of diazepam-binding inhibitor correlate with REM latency in schizophrenia, a pilot study. 788 20

Although the pathogenesis of schizophrenia is unknown, there are data which indicate that the disease may be due to neurodevelopmental disturbances. Cell recognition molecules such as N-CAM and L1 antigen are involved in cell-cell interactions during development and in plasticity of the nervous system and could therefore be altered in relation to ongoing or established pathological processes. Using the Western blot technique, we found significant increases in N-CAM immunoreactive proteins and decreases in L1 antigen in the CSF of schizophrenic patients as compared to normal controls. The decrease in L1 antigen was observed in the 140-kDa band, and N-CAM was increased only in the 120-kDa band. The 120-kDa band of N-CAM and the 140-kDa band of L1 antigen were prominent components of CSF, but in serum these bands were minor or not detectable. Neuroleptic treatment did not significantly change either N-CAM or L1 antigen concentrations in CSF. It is possible that these CSF proteins are derived from CNS cells as secreted soluble N-CAM isoforms and L1 peptides. Our results suggest the possibility of a specific pattern of abnormal cellular function in the CNS in schizophrenia.
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PMID:Disturbances in cell recognition molecules (N-CAM and L1 antigen) in the CSF of patients with schizophrenia. 789 25

Levels of CSF fluid interleukin-2, but not interleukin-1 alpha, were found to be higher in 10 neuroleptic-free schizophrenic patients than in 10 healthy subjects matched for sex and age. Because interleukin-2 increases dopaminergic neurotransmission and participates in autoimmunity and cell growth, the authors postulate that elevated levels of central interleukin-2 might contribute to the increased dopaminergic neurotransmission, autoimmune phenomena, and abnormal brain morphology described in some patients with schizophrenia.
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PMID:Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients. 810 12

Diazepam-binding inhibitor (DBI) is a 9-kD neuropeptide that interacts with the benzodiazepine (BZD) binding sites of the neuronal gamma-aminobutyric acid type A (GABAA) receptor and with the glial mitochondrial BZD receptor (MBR). We explored the involvement of CSF DBI-LI in schizophrenia, based on the potential role of GABA in the negative symptoms associated with schizophrenia, the relationship of its receptors with dopamine and norepinephrine release, and the proposed therapeutic efficacy of BZDs in schizophrenia. Clinical data, CSF DBI-LI and CSF monoamine measures were obtained in 65 drug-free male chronic (DSM-IIIR) schizophrenic patients, 53 of whom were also tested prior to haloperidol withdrawal. Following haloperidol withdrawal, CSF DBI-LI increased significantly. Drug-free CSF DBI-LI did not correlate with CSF monoamines. CSF DBI-LI was significantly higher in paranoid compared to chronic undifferentiated schizophrenic patients. The data suggest that DBI may have a symptom modulatory rather than an etiological role in schizophrenia.
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PMID:CSF diazepam binding inhibitor and schizophrenia: clinical and biochemical relationships. 827 78

Using C8 reversed-phase HPLC in conjunction with sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we have fractionated proteins contained in human CSFs obtained from patients with schizophrenic disorders. When these proteins were electrophoretically blotted onto polyvinylidene difluoride membrane for direct N-terminal amino acid sequencing, several CSF proteins were identified; these included albumin, transferrin, apolipoprotein A-I, beta 2-microglobulin, and prealbumin. We have also identified two structurally related human CSF proteins designated cerebrin 28 (M(r) 28,000) and cerebrin 30 (M(r) 30,000) that have an N-terminal amino acid sequence of NH2-APPAQVSVQPNF and NH2-APEAQVSVQPLFXQ, respectively. Comparison of these sequences with existing database at Protein Identification Resource (R 32.0), GenBank (R 72.0), SWISS-PROT (R 22.0), and EMBL (R 31.0) indicated that they are unique proteins. These proteins were subsequently purified by high performance electrophoresis chromatography (HPEC) using an Applied Biosystems 230A HPEC system. A specific polyclonal antibody was prepared and an ELISA was established for cerebrin 30. It was noted that HPEC is a powerful tool to purify microgram quantities of proteins from human, rabbit, and rat CSFs. Using such a system, we have been able to micropurify as many as 10 proteins simultaneously in a single experiment because the elution of proteins occurred strictly according to their molecular weights. More importantly, we routinely obtained a recovery of > 90%. The potential use of this technology for micropurification of proteins was discussed.
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PMID:Micropurification of two human cerebrospinal fluid proteins by high performance electrophoresis chromatography. 833 40

The KSV model of the schizophrenias proposes that up to 70% of schizophrenics have a pathogenic allele, or abnormal expression, of the KALIG-1 gene which is located at Xp22.3. This gene encodes a nerve-cell adhesion molecule (N-CAM) like protein, and is deleted in 66% of patients with Kallmann's syndrome, anosmia with secondary hypogonadism. Although superficially distinct, the schizophrenias and Kallmann's syndrome show numerous parallel trait defects which occur with a similar sex distribution. These defects are usually more profound in Kallmann's syndrome. Occasionally, Kallmann's patients exhibit additional defects, such as ichthyosis, which are due to the further deletion or translocation of adjacent genes. Since schizophrenics exhibit virtually all known trait defects in Kallmann's except these, it suggests that the aberrant genes are defective, but not deleted in schizophrenia. It also appears that compensatory mechanisms, involving serine proteases, are active in schizophrenia, which largely preserve fertility, but at the expense of an increased vulnerability to develop a psychosis by an episodic disruption of the blood-CSF barrier. Consequently, schizophrenia is rare in Kallmann's patients, while most schizophrenics are capable of reproduction.
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PMID:The Kallmann's syndrome variant (KSV) model of the schizophrenias. 846 Dec 65

1. It has been postulated that the interrelated processes of neurodegeneration, neuroplasticity, and neuroimmunological abnormalities may play a role in the pathophysiology of schizophrenia. Since, interleukins are produced in the central nervous system and have cytokine and growth promoting properties, they are an obvious choice to consider in these neural processes. 2. Cerebrospinal fluid obtained from schizophrenic patients, on and off medications, and from normal controls was assayed for interleukin-1 alpha (IL-1 alpha) and interleukin-2 (IL-2) using a sensitive enzyme-linked immunoassay. 3. IL-1 alpha concentration were below the detection limits of the assay in both controls and schizophrenics. 4. IL-2 levels were under 1 ng/ml CSF in nearly all subjects. There was no significant difference in IL-2 levels between medicated and medication-free schizophrenics or when patients were compared to controls.
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PMID:Interleukin-1 alpha and interleukin-2 in cerebrospinal fluid of schizophrenic subjects. 847 20


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