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 relatively high comorbidity of type 2 diabetes and schizophrenia may suggest a shared biological susceptibility to these two conditions. Family studies have demonstrated an increased risk of diabetes in unaffected relatives of patients with schizophrenia, consistent with a heritable susceptibility trait. Linkage analyses have identified several loci that are associated with schizophrenia and some of these, notably those on chromosomes 2p22.1-p13.2 and 6g21-824.1 have also been observed in linkage studies in type 2 diabetes. In addition, the dopamine D5 receptor on chromosome 5 and the tyrosine hydroxylase gene on chromosome 11 have both been suggested as candidate genes in schizophrenia and may also be implicated in susceptibility to poor glycaemic control. In addition, an increased rate of type II diabetes has been observed in some patients treated with antipsychotics. Potential neurochemical substrates of this effect include the histamine H1 receptor, the 5-HT2C serotonin receptor or the beta3 adrenoreceptor. However, the search for a genetic basis to the association between diabetes and schizophrenia is still in its infancy, and much further work needs to be performed, including the systematic screening of all confirmed susceptibility loci and quantitative trait locus mapping of glycaemic control.
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PMID:Schizophrenia, antipsychotics and diabetes: Genetic aspects. 1645 47

We evaluated the activity of the atypical antipsychotic drug olanzapine on differentiation and gene expression in adult neural precursor cells in vitro. Neural precursors obtained from forebrain subventricular zone (SVZ)-derived neurospheres express a subset (13/24) of receptors known to bind olanzapine at high to intermediate affinities; in contrast, all 24 are expressed in the SVZ. In the presence of 10 nM, 100 nM or 1 microM olanzapine, there is no significant change in the frequency of oligodendrocytes, neurons, GABAergic neurons and astrocytes generated from neurosphere precursors. In parallel, there is no apparent change in cell proliferation in response to olanzapine, based upon bromodeoxyuridine incorporation. There are no major changes in cytological differentiation in response to the drug; however, at one concentration (10 nM) there is a small but statistically significant increase in the size of glial fibrillary acidic protein-labeled astrocytes derived from neurosphere precursors. In addition, olanzapine apparently modulates expression of one serotonin receptor -- 5HT2A -- in differentiating neurosphere cultures; however, it does not modify expression of several other receptors or schizophrenia vulnerability genes. Thus, olanzapine has a limited influence on differentiation and gene expression in adult neural precursor cells in vitro.
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PMID:Limited influence of olanzapine on adult forebrain neural precursors in vitro. 1656 41

The aim of this study was to examine the influence of different fat diets on serotonin receptor and transporter binding. Male Sprague-Dawley rats were fed a diet of either high saturated fat, omega-6 polyunsaturated fatty acid, omega-3 polyunsaturated fatty acid or low fat (control) for eight weeks. Using Beta-Imager quantification techniques, [(3)H]ketanserin, [(3)H]mesulergine and [(3)H]paroxetine binding to serotonin (5-HT)(2A), 5-HT(2C) receptors and 5-HT transporters (5-HTT) was measured throughout the brain in all four groups. All three high fatty acid diets influenced serotonin receptor binding, however the most pronounced effects were that compared with the low fat control group, i) 5-HT(2A) receptor binding was increased in the caudate putamen, but reduced in the mammillary nucleus in high saturated fat and high omega-6 polyunsaturated fatty acid diet groups; ii) 5-HT(2C) receptor binding was reduced in the mamillary nucleus of saturated fat group and reduced in prefrontal cortex of the omega-6 polyunsaturated fatty acid and omega-3 polyunsaturated fatty acid groups; and iii) 5-HTT binding was reduced in the hippocampus in the omega-6 polyunsaturated fatty acid group. Overall, the omega-6 polyunsaturated fatty acid diet exerted the most influence on serotonin receptor and transporter binding. These results may be of importance in relation to neuropsychiatric diseases such as schizophrenia, where associations between altered fatty acid levels and the serotonergic system have been made.
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PMID:Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain. 1660 May 14

Since the 1950s, when serotonin (5-HT) was discovered in the mammalian central nervous system (CNS), an enormous amount of experimental evidence has revealed the pivotal role of this biogenic amine in a number of cognitive and behavioural functions. Although 5-HT is synthesized by a small group of neurons within the raphe nuclei of the brain stem, almost all parts of the CNS receive serotonergic projections. Furthermore, the importance of 5-HT modulation and the fine-tuning of its action is underlined by the large number of 5-HT binding sites found in the CNS. Hitherto, up to 15 different 5-HT receptors subtypes have been identified. This review was undertaken to summarize the work that has explored the pathophysiological role of one of these receptors, the 5-HT2C receptor, that has been emerged as a prominent central serotonin receptor subtype. The physiology, pharmacology and anatomical distribution of the 5-HT2C receptors in the CNS will be firstly reviewed. Finally, their potential involvement in the pathophysiology of depression, schizophrenia, Parkinson's disease and drug abuse will be also discussed.
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PMID:Central serotonin2C receptor: from physiology to pathology. 1701 66

Since the late 1950s, appreciation of dopamine receptor blockade has played a primary role in understanding the mechanism underlying the therapeutic effects of antipsychotic drugs in schizophrenic patients in treating the positive symptoms of schizophrenia (e.g., delusions and hallucinations). Development of the second generation of antipsychotic drugs, otherwise known as atypical antipsychotic drugs, has resulted in treatments with improved subjective tolerability but relatively modest improvements in the negative symptoms of schizophrenia such as avolition, flat affect, and anhedonia. The major current challenge is to develop medications which can further improve negative symptoms treatment and also tackle the intractable clinical problems of cognitive impairment associated with schizophrenia. Further advances along these lines with respect to the dopaminergic and serotonergic neurostransmitter systems will be aided by an appreciation of the interaction between dopamine and serotonin receptor subtypes in a range of key brain structures, such as the prefrontal cortex, thalamus, striatum, amygdala, hippocampus, and the brain stem nuclei, from which the cell bodies of monoaminergic-containing neurons originate. Increasing emphasis on the use of animal models which are homologous to critical aspects of the pathophysiology in the brains of schizophrenic patients will also be required, especially as negative symptoms and cognitive impairment become an important focus for generating novel therapeutics.
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PMID:Serotonin and dopamine interactions in rodents and primates: implications for psychosis and antipsychotic drug development. 1734 61

To clarify nosologic differences between schizoaffective psychosis (SAP) and attack-like progressive schizophrenia at molecular-genetic level, the genetic polymorphism of serotonin receptor type 2A (5HTR2A), serotonin transporter (5-HTTLRP), and brain-derived neurotrophic factor (BDNF) was studied in 563 patients with schizophrenia (mean age 37.7+/-14.4 years, age at disease onset 26.7+/-11.4 years), and 171 patients with SAP (mean age 30.7+/-11.6 years, age at disease onset 24.9+/-8.5 years). The control group consisted of 536 psychiatrically well subjects. Clinical symptoms and personal features were evaluated as well. By comparison with schizophrenic patients, those with SAP were featured by subtle negative symptoms and personality changes that supported the evidence that SAP is a disorder with a favorable outcome. Molecular-genetic studies revealed higher frequencies of S allele and SS genotype (5-HTTLPR polymorphism), which are thought to be associated with depression and depressive symptoms, and higher frequency of BDNF genotypes, containing Met allele, in combination with 5-HTTLRP genotypes containing L allele, in patients with SAP as compared to the schizophrenic group. C allele and CC genotype (T102C 5-HTR2A polymorphism) frequencies were higher in both groups of patients vs. controls. In conclusion, the results confirm the concept considering SAP an independent nosologic category.
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PMID:[The molecular-genetic aspects of differentiation of schizoaffective psychosis and attack-like progressive schizophrenia]. 1750 Feb 7

The proportion of treatment-resistant schizophrenia (TRS) has been estimated as 20-40% in the schizophrenic patients. Genetic factors are considered to be involved in the development of this condition. Serotonin subtypes are hypothesized to be the candidate genes. In the present study, single marker and haplotype analyses between several mutations of serotonin receptor subtypes (HTR2A, HTR3A and HTR4) and TRS (TRS=101, NON-TRS=239) were performed to determine a possible relationship with the development of TRS. Additionally, we also compared the daily neuroleptic dosage among each genotype. No significant association was observed between TRS and each allele, genotype, and haplotype. However, the daily neuroleptic dosage that patients had been receiving during their maintenance therapy was significantly higher in patients with the T/T genotype of HTR3A polymorphism (rs1062613, p=0.041). The present results support further research to examine the relationship between HTR3A polymorphism and the development of TRS in the Japanese population.
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PMID:Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population. 1835 59

The frequency of obesity, insulin resistance, type 2 diabetes mellitus and other components of metabolic syndrome appear to be significantly elevated in some psychiatric patients. This is a notable example of genetic/environment interaction. Considering the genetic contribution, evidence of insulin resistance in persons with schizophrenia was reported in the pre-pharmacological era. High insulin, glucose, and cortisol levels are observed in first episode psychosis. The frequency of type 2 diabetes mellitus is significantly increased in persons with schizophrenia and bipolar disorder and in their first-degree relatives. Finally, a link exists between schizophrenia and enzymes involved in glycolysis and between antipsychotic drug-induced weight gain and serotonin receptor polymorphism. Important environmental factors are poor dietary habits, smoking, lack of physical exercise, and drug treatment, mostly with antipsychotic drugs (APDs) and perhaps with mood stabilizers. The APDs probably induce metabolic dysfunction by producing sudden appetite increase and weight gain in predisposed subjects. However, direct drug effects on glucose and lipid metabolism independent from body weight change have been proposed. Excessive weight gain is mainly observed with clozapine, olanzapine, chlorpromazine, and thioridazine and is less consistently noted with risperidone or quetiapine. Two recently introduced APDs, ziprasidone and aripiprazole, display a neutral effect on weight and metabolism. Subjects at high risk must be identified early during APD treatment so that provide lifestyle counseling and pharmacological assistance can be provided. The immediate research agenda for the APDs is to improve the animal models of drug-induced metabolic dysfunction; to clarify mechanisms other than weight gain and appetite stimulation; and to test pharmacological agents in randomized, double-blind studies to prevent or reverse metabolic syndrome in selected patients.
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PMID:The metabolic syndrome during atypical antipsychotic drug treatment: mechanisms and management. 1837 Jun 98

The serotonin 5-HT2C receptor is a G-protein-coupled receptor and is one of the 14 subtypes that constitutes the serotonin receptor family. Agonists of 5-HT2C have been implicated as potential treatments for diseases of significant unmet medical need, including obesity and schizophrenia. Despite approximately 10 years of discovery efforts, 5-HT2C agonists have only recently advanced into the clinic, likely because many of the early drug discovery efforts experienced significant difficulties with attaining receptor selectivity. Several of these issues related to receptor selectivity have now been overcome, resulting in the entry of compounds into advanced clinical trials. This review summarizes the progress in 5-HT2C agonist discovery and clinical development over the last 3 years. [sw1]what are the several issues - several issues relating to receptor selectivity?
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PMID:Agonists of the serotonin 5-HT2C receptor: preclinical and clinical progression in multiple diseases. 1860 May 61

Asenapine, a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has high affinity for a wide range of receptors, including the serotonergic receptors 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT( 2B), 5-HT(2C), 5-HT(5A), 5-HT(6) and 5-HT( 7). We examined the long-term effects in rat brain of multiple doses of asenapine on representative serotonin receptor subtypes: 5-HT(1A), 5-HT(2A) and 5-HT(2C). Rats were given asenapine (0.03, 0.1 or 0.3 mg/kg) subcutaneously twice daily or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex (DFC), caudate putamen, nucleus accumbens, hippocampal CA( 1) and CA(3) regions, and entorhinal cortex and processed for in-vitro receptor autoradiography. Asenapine 0.1 and 0.3 mg/kg significantly increased 5-HT(1A) binding in mPFC (by 24% and 33%, respectively), DFC (27%, 31%) and hippocampal CA(1) region (23%, 25%) (all P < 0.05). All three asenapine doses (0.03, 0.1 and 0.3 mg/kg) significantly decreased 5-HT(2A) binding by a similar degree in mPFC (40%, 44%, 47%, respectively) and DFC (45%, 51%, 52%) (all P < 0.05), but did not alter 5-HT(2A) binding in the other brain regions studied. In contrast to the effects on 5-HT(1A) and 5-HT(2A) receptors, asenapine did not alter 5-HT(2C) binding in any brain region examined at the doses tested. Our results indicate that repeated administration of asenapine produces regional-specific effects on 5-HT(1A) and 5-HT(2A) receptors in rat forebrain regions, which may contribute to the distinctive psychopharmacologic profile of asenapine.
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PMID:Asenapine induces differential regional effects on serotonin receptor subtypes. 1871 49


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