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)

Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact that antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT2a receptor antagonists and relatively weaker dopamine D2 antagonists. These agents share in common low extrapyramidal side effects at clinically effective doses and possibly greater efficacy to reduce negative symptoms. As a group, they also have a superior effect on cognitive function and greater ability to treat mood symptoms in both patients with schizophrenia or affective disorders than typical antipsychotic drugs. The atypical antipsychotic agents vary in their affinities for other types of 5-HT as well as dopamine, muscarinic, adrenergic, and histaminic receptors, some, or all of which, may contribute to their differences in efficacy and side effect profile. Of the other 5-HT receptor which these drugs directly, the 5-HT1a and 5-HT2c receptors are the strongest candidates for contributing to their antipsychotic action and low EPS profile. The 5-HT6 and 5-HT7 receptors may also be of some importance. Stimulation of the 5-HT1a receptor appears to produce many of the same effects as antagonism of the 5-HT2a receptor while antagonism of the 5-HT2c receptor appears to diminish some of the actions of 5-HT2a receptor antagonism. Future antipsychotic drug development can include targeting multiple serotonin receptor subtypes.
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PMID:The role of serotonin in antipsychotic drug action. 1043 96

The novel serotonin receptor subtypes, 5-HT6 and 5-HT7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics. These factors have led some to speculate about the involvement of 5-HT6 and 5-HT7 receptors in schizophrenia. However, relatively little is known about these receptor subtypes, including the regulation of their expression in limbic regions. In particular, the regulation of extracellular serotonin levels in the striatum and hippocampal formation by glutamate receptors led us to examine the effects of systemic ionotropic glutamate receptor modulator treatment on 5-HT6 and 5-HT7 receptor expression in these regions. MK-801 treatment induced a dose-dependent decrease in striatal 5-HT6 receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT6 receptor mRNA levels. Hippocampal 5-HT6 and 5-HT7 receptor expression were not dramatically affected by any of the treatments. To our knowledge, this is the first demonstration of the regulation of striatal 5-HT6 receptor mRNA expression, and provides neurochemical anatomical evidence for the interaction of serotonergic and glutamatergic systems. Furthermore, although these two neurotransmitter systems are separately implicated in schizophrenia, the glutamatergic regulation of the expression of a receptor subtype associated with schizophrenia suggests that alterations in serotonin receptor expression in schizophrenia may result, in part, from altered glutamatergic activity.
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PMID:Ionotropic glutamate receptor modulation of 5-HT6 and 5-HT7 mRNA expression in rat brain. 1045 31

Cyclic AMP-responsive element-binding protein (CREB) is one of the messenger molecules involved in intracellular signal transduction pathways used by most dopamine and serotonin receptor subtypes. In addition, CREB stimulates the expression of a number of genes, alterations in the expression of which may be associated with schizophrenia. The promoter region of the human CREB gene was therefore analyzed to identify genetic variants that may lead to the modification of CREB expression and contribute to schizophrenia. Eighty unrelated schizophrenics and 100 healthy controls were screened for genetic variants of the CREB gene by SSCP analysis, followed by direct sequencing of PCR products. Two novel variants (-933T-->C and -413G-->A) were found only in schizophrenics. A patient with the -933T-->C variant had unusual clinical characteristics in addition to typical schizophrenic symptoms.
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PMID:Novel variants in the promoter region of the CREB gene in schizophrenic patients. 1057 Sep 22

The serotonin receptor type 2A (5-HT2A) is a primary candidate for involvement in major psychoses. Polymorphisms within the 5-HT2A gene have recently been reported to be associated with a variety of psychopathological conditions. In the present study, we investigated the potential influence of the T102C polymorphism on the psychopathology of schizophrenia. One hundred eighty-eight inpatients affected by schizophrenia (DSM-III-R) were assessed by the Operational Criteria checklist for psychotic illness (OPCRIT) and were typed for their 5-HT2A variants by PCR techniques. Mania, depression, delusion and disorganization were the four symptomatologic factors previously derived from our psychotic population that were used to define phenotype in our sample. Genetic variants of the polymorphism under study were not associated with these symptomatologic factors, and consideration of possible stratification effects such as sex and age of onset did not reveal any association either. Our results do not, therefore, support the hypothesis that the serotonin receptor 2A gene is a liability factor for the symptomatology of schizophrenia as defined by the OPCRIT checklist. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:84-87, 2000.
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PMID:Serotonin-2A receptor gene is not associated with symptomatology of schizophrenia. 1068 58

Epidemiological and genetic studies of alcoholism and schizophrenia have been performed, and in this study, the human serotonin receptor (HTR2) polymorphism was examined in 75 alcoholics and 31 schizophrenic patients. We found that there might not be a significant difference between these psychiatric disease patients and controls in the frequency of the C1/C2 HTR2 gene (MspI polymorphism). The results suggest that the human HTR2 MspI polymorphism might not be associated with a risk factor for developing alcohol dependence or susceptibility to schizophrenia. It is possible that there may be a racial difference in the frequency of the C1/C2 gene between Japanese and Caucasians. Further studies are required to determine whether or not the novel serotonin receptor polymorphism reflects the pathogenesis of alcoholism or schizophrenia.
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PMID:The human serotonin receptor gene (HTR2) MspI polymorphism in Japanese schizophrenic and alcoholic patients. 1075 25

The introduction of conventional antipsychotics revolutionized the management of psychotic disorders in the 1950s. The use of these agents has been marked by several shortcomings, including their association with severe motor disturbances and their limited efficacy in treating the negative and cognitive symptoms of schizophrenia. Patients noncompliance has largely been the result of subjectively distressing extrapyramidal motor side-effects (EPMS). It was therefore necessary to develop antipsychotic drugs with selective pharmacological profiles, e.g. limbic selectivity. A defining characteristic of atypical neuroleptics is a higher ratio of serotonin receptor blockade to D2 receptor blockade. Their primary advantage is their superior side-effect profile. The implications of EPMS reduction touch several domains of pathology in schizophrenia such as short- and long-term movement disorders, noncompliance, relapse rate, negative symptoms and cognitive dysfunction. Novel antipsychotics may represent the second pharmacological revolution in the treatment of psychotic disorders. There is, however, still a need for a critical evaluation of the risk-benefit-ratio of differing atypical agents.
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PMID:[Atypical neuroleptics: new approaches to drug therapy of schizophrenic disorders]. 1120 12

Clinical studies have shown that there is a genetic contribution to the pathogenesis of schizophrenia. The molecular mechanisms of effective antipsychotic drugs and recent advances in neural development suggest that several dopamine receptor, serotonin receptor and neurotrophic factor genes might be involved in the disorder. In this study, we assessed the associations between schizophrenia and polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3), the serotonin 2A receptor (5HTR2A), the brain-derived neurotrophic factor (BDNF), the ciliary neurotrophic factor (CNTF) and the neurotrophin-3 (NT-3) genes. Our results suggest that the polymorphisms at the DRD3, 5HTR2A, CNTF and BDNF gene loci are unlikely to make our sample more genetically susceptible to schizophrenia. However, we found significant differences in microsatellite allele frequencies between schizophrenic and control groups for DRD2 in the whole sample and for DRD2 and NT-3 only in women. Therefore, clinical differences in the presentation of schizophrenia between gender might be related to genetic factors.
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PMID:Association study of schizophrenia with polymorphisms at six candidate genes. 1134 65

The 5HT2C receptor has a high affinity for clozapine, a nontypical neuroleptic, and has therefore been postulated to play a role in mediating negative symptoms and neuroleptic response in schizophrenia. In the current study, the Cys23Ser 5HT2C serotonin receptor polymorphism was examined for linkage to schizophrenia by genotyping 207 nuclear families consisting of both parents and schizophrenic child and using the transmission disequilibrium test to examine possible preferential transmission of these alleles from 68 heterozygous mothers to their ill child. No evidence was obtained for preferential transmission of the Cys23Ser 5HT2C alleles in schizophrenia in either of the two main ethnic groups examined (German and Palestinian Arab) or in the combined cohort (TDT chi-square = 0.00, NS).
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PMID:A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia. 1135 41

Genetic polymorphism of the serotonin receptor (5-HTR2A) gene has been reported to be associated with the expression of clinical signs characteristic of major psychoses, including schizophrenia and affective disorders. In this study, personality traits of patients with these diseases and the associations of these traits with 5-HTR2A allelic polymorphisms were studied. It was demonstrated that schizophrenic and affective patients with the 2/2 genotype of serotonin receptor had lower scores on the anxiety scale and on the anxiety-related hypochondriasis and neuroticism scales than subjects with the 1/1 and 1/2 genotypes.
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PMID:[Serotonin type 2a (5-HTR2A) receptor gene polymorphism and personality traits in patients with endogenous psychoses]. 1142 Nov 30

Both antidepressants and neuroleptics are widely used in psychopharmacological treatment. In view of the often equal efficacy of substances belonging to the same class of drugs, potential side effects have become the most important criteria for the selection of a specific drug. The therapeutic effect of antidepressants is mediated by their inhibition of the reuptake of the neurotransmitters noradrenaline and of serotonin. Significant adverse effects may occur through the interaction of the antidepressants with other receptors believed not to be related to the therapeutic action, most importantly the muscarinic acetylcholine receptor (M), the histamine-1 (H1) receptor and the alpha-1 (alpha 1) adrenergic receptor. In contrast to the classical tricyclic antidepressants, the newly available selective serotonin reuptake inhibitors neither block the M1-, H1- nor the alpha 1 receptors. Although the rate of side effects is considerably lower compared to tricyclic antidepressants, adverse effects may, however, occur through the stimulation of different serotonin receptor subtypes (5-HT2A, 5-HT2B, and 5-HT3), leading to anxiety, sleep disturbances and nausea. Neuroleptics are often administered for years or even decades in the treatment of schizophrenia or schizoaffective disorder. The main adverse effects are extrapyramidal symptoms, including parkinsonism, akathisia, dystonic reactions, and tardive dyskinesias. With the introduction of the atypical neuroleptics (e.g. clozapine, risperidone, olanzapine) it became apparent that the antipsychotic effect and the extrapyramidal unwanted effect are not always and inextricably linked. The evidence for the hypotheses of the pathogenetic mechanisms leading to extrapyramidal side effects is reviewed. Both the dopamine receptor hypersensitivity hypothesis and the hypothesis of mitochondrial respiratory chain inhibition are as yet based on indirect evidence. However, if, as suggested by the analyses of mitochondrial energy metabolism, the antipsychotic effect and the adverse effects are unrelated properties of neuroleptics, new principles should be applied in the development of novel neuroleptics. Neuroleptics might then be developed that are effectively antipsychotic but are less likely to produce limiting extrapyramidal side effects.
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PMID:Cell-mediated side effects of psychopharmacological treatment. 1171 30


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