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)

Clozapine is a potent atypical neuroleptic or antipsychotic agent used to relieve symptoms of early-diagnosed schizophrenia. Aside from well-described dopamine and serotonin receptor blockade effects, clozapine may also be neuroprotective through its modulation of the p75 neurotrophin receptor (p75(NTR)) and superoxide dismutase 1 (SOD1) expression. The death-signalling activities of both p75(NTR) and mutant SOD1 are implicated in motor neuron degeneration in humans and transgenic mice with amyotrophic lateral sclerosis (ALS). We therefore investigated the effects of clozapine in cell culture and mouse models of ALS. Clozapine dose-dependently inhibited full-length and cleaved p75(NTR) but not SOD1 protein expression in the motor neuron-like (NSC-34) cell line. Furthermore, low concentrations of clozapine protected NSC-34 cells from paraquat-mediated superoxide toxicity, nerve growth factor (NGF)-induced death signalling, and serum deprivation, whereas high concentrations potentiated death. Systemic thrice-weekly administration of low and high-dose clozapine to mutant superoxide dismutase 1 (SOD1(G93A)) mice produced differential effects on disease onset and survival. Low-dose treatment was associated with delayed locomotor impairment and death, compared to high-dose clozapine, which accelerated paralysis and mortality (P < 0.05). Increased death was not attributable to toxicity, as clozapine-induced agranulocytosis was not detected from blood analysis. High-dose clozapine, however, produced extrapyramidal symptoms in mice manifest by hindlimb rigidity, despite reducing spinal cord p75(NTR) levels overall. These results suggest that although clozapine may exert p75(NTR)-mediated neuroprotective activity in vitro, its profound antagonistic effects on dopaminergic and serotonergic systems in vivo at high doses may exacerbate the phenotype of transgenic ALS mice.
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PMID:Opposing effects of low and high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice. 1459 5

The major targets of current drugs used in mental health, such as neurotransmitter receptors and transporters, are based on serendipitous findings from several decades ago, and there is currently a severe drought of new drug targets. There is a pressing need for novel drugs, and much hope has been placed on the use of molecular genetics to help define them. However, despite evidence for a genetic basis to schizophrenia stretching back for over a century, and a heritability of about 80%, the identification of susceptibility genes has been an uphill struggle. Candidate gene studies, which have generally focussed on obvious candidates from the dopamine and serotonin systems, as well as genes involved in brain development, have not generally been successful, although meta-analysis indicates that the dopamine D3 receptor gene (DRD3) and the serotonin receptor gene type 2A (HTR2A) may have a very small influence on risk. Linkage analysis has provided robust evidence of genetic loci, for example, on chromosomes 8p, 13q and 22q, and also implies shared genetic aetiology with bipolar disorder. The identification of these loci together with advances in genetic technology, especially the characterisation of polymorphisms, the understanding of haplotypes and the development of statistical methods, has lead to the identification of several plausible susceptibility genes, including neuregulin 1, proline dehydrogenase and dysbindin. Interestingly, these genes point more towards a role for the glutamate pathway rather than the dopamine pathway in schizophrenia. We have attempted to replicate some of these findings in schizophrenic patients from SW China, and we find significant association with a novel neuregulin 1 haplotype, with proline dehydrogenase polymorphisms, but not with catechol-O-methyltransferase (COMT). The replication of neuregulin 1 association on chromosome 8p by several investigators is the most convincing to date, and the presence of a syndrome similar to dementia praecox of 8p linked families, and the lack of linkage of bipolar disorder to this region is a testament to the ideas of Kraepelin more than 100 years ago.
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PMID:The genetics of schizophrenia: glutamate not dopamine? 1462 61

Serotonin 2C receptor (5-HT2CR) heterogeneity in the brain occurs mostly from two different sources: (i) 5-HT2CR mRNA undergoes adenosine-to-inosine editing events at five positions, which leads to amino acid substitutions that produce receptor variants with different pharmacological properties; (ii) 5-HT2CR mRNA is alternatively spliced, resulting in a truncated mRNA isoform (5-HT2CR-tr) which encodes a non-functional serotonin receptor. 5-HT2CR mRNA editing efficiencies and the expression of the full-length and the truncated 5-HT2CR mRNA splice isoforms were analyzed in the prefrontal cortex of elderly subjects with schizophrenia vs. matched controls (ns = 15). No significant differences were found, indicating that there are no alterations in editing or alternative splicing of 5-HT2CRs that are associated with schizophrenia in persons treated with antipsychotic medications. Quantitation of 5-HT2CR and 5-HT2CR-tr mRNA variants revealed that the expression of 5-HT2CR-tr was approximately 50% of that observed for the full-length isoform.
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PMID:RNA editing and alternative splicing of human serotonin 2C receptor in schizophrenia. 1471 96

The review considers the most interesting data on the molecular genetic basis of mental disorders and personality traits, which were obtained within the framework of the Russian program Human Genome. Polymorphic markers Taq1A of the dopamine receptor gene and T102C of the serotonin receptor type 2A gene were associated with schizophrenia, in particular, chronic forms with poor prognosis. In mentally healthy people, the insertion/deletion polymorphism of the serotonin transporter gene was associated with schizoid traits.
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PMID:[Genomics in psychology and psychiatry]. 1504 46

Central dopamine-2 (D2) receptors are importantly involved in the pathogenesis and treatment of schizophrenia. Central D2 receptors are also involved in thermoregulation. Recently, a type of central nervous system proportional control thermostat was described that governs the magnitude of several serotonin receptor-mediated core body thermoregulatory responses in proportion to both the amount of nocturnal melatonin secreted and the minimum level of nocturnal core body temperature (Tmin). The present study investigated whether the magnitude of D2 receptor-mediated hypothermia--a putative index of central D2 receptor sensitivity--is also regulated by this proportional control thermostat in humans. Twenty healthy subjects had their 02:00 h melatonin concentrations (MT2am) and Tmin measured during consecutive sleep episodes and their core body temperature responses (TAUC) measured the next two mornings after oral ingestion of either the D2 receptor agonist bromocriptine 3.125 mg or placebo. We found that the bromocriptine-induced TAUC was significantly and independently correlated with both Tmin and MT2am. In conclusion, D2 receptor-mediated hypothermia, an index of central D2 receptor sensitivity, is regulated by a proportional control thermostat in humans. The abnormal D2 receptor function in schizophrenia could be related to dysfunction of this thermostat.
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PMID:Regulation of central dopamine-2 receptor sensitivity by a proportional control thermostat in humans. 1526 1

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) mediates a multitude of central nervous functions by activating 5-HT receptor subtypes. A dysfunction of serotonergic neurotransmission is considered to play a major role in the pathophysiology of complex neuropsychiatric disorders. In our study, a mutation screen of the serotonin receptor gene HTR3B was carried out to explore a putative contribution to the etiology of bipolar affective disorder (BPAD) and schizophrenia (SZ). Screening of 49 patients suffering from BPAD, 78 patients with SZ and 62 control individuals revealed eleven sequence variations including a 3 bp deletion within the 5'UTR (5' untranslated region), four exonic and five intronic SNPs as well as a point mutation in the 3'UTR of HTR3B. Four of these sequence variations have not been described previously. Statistical computation rated most variants as probably non-disease related polymorphisms. However, IVS6 + 31C > T, IVS6 + 40C > A, and 1386T > C were solely detected in bipolar affective patients and in none of the controls. Interestingly, we observed a significant underrepresentation of the 3 bp deletion -100_-102delAAG in an extended sample of 162 bipolar affected patients compared to controls (allele-wise: 8% vs. 15%, P = 0.006, OR = 0.49, 95% CI: 0.3-0.82; genotype-wise: 15,5% vs. 29,0%, P = 0.005, OR = 0.45, 95% CI: 0.26-0.77). We suggest that this deletion may influence translational efficiency, thereby possibly affecting the development of bipolar affective disease.
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PMID:Investigation of the human serotonin receptor gene HTR3B in bipolar affective and schizophrenic patients. 1538 65

This study was to aim at investigating the potential interaction for the serotonin receptor gene (5-HTR) 2A and serotonin transporter gene (5-HTTLPR) polymorphisms in the development of schizophrenia, as well as the interaction of the two polymorphisms in relation with symptomatology, family history, age of onset and antipsychotic response. Genomic DNA analysis with polymerase chain reaction (PCR) was used for the genotyping. One hundred and eleven (111) patients with schizophrenia and 172 normal controls participated in the study. We did not find any association between the individual polymorphism and schizophrenia. The significant interaction effect between 5-HTTLPR and 5-HTR2A polymorphisms on the development of schizophrenia as well as on the antipsychotics response, family history, symptomatology and age at onset, was not found. However, subject with 5-HTR2A*TT genotype were found to have lower age of onset, compared to their counterparts (p=0.01). These results suggest that the interaction between 5-HTTLPR and 5-HTR2A polymorphisms may not contribute to susceptibility to schizophrenia as well as some clinical factors such as antipsychotic response, at least in the Korean population.
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PMID:No evidence for interaction between 5-HT2A receptor and serotonin transporter genes in schizophrenia. 1589 80

This review addresses the relationship between modifications in membrane phospholipid composition (MPC) and alterations in dopaminergic, serotonergic and cholinergic neurotransmitter systems in schizophrenia. The main evidence in support of the MPC hypothesis of schizophrenia comes from post-mortem and platelet studies, which show that in schizophrenia, certain omega-3 and omega-6 polyunsaturated fatty acid (PUFA) levels are reduced. Furthermore, examination of several biochemical markers suggests abnormal fatty acid metabolism may be present in schizophrenia. Dietary manipulation of MPC with polyunsaturated fatty acid diets has been shown to affect densities of dopamine, serotonin and muscarinic receptors in rats. Also, supplementation with omega-3 fatty acids has been shown to improve mental health rating scores, and there is evidence that the mechanism behind this involves the serotonin receptor complex. This suggests that a tight relationship exists between essential fatty acid status and normal neurotransmission, and that altered PUFA levels may contribute to the abnormalities in neurotransmission seen in schizophrenia.
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PMID:Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia. 1600 34

Aripiprazole is a new chemical entity with a unique pharmacological profile. It has strong affinities for certain dopamine receptors, and intermediate affinity for serotonin, adrenergic and histamine receptors. Partial agonism of the D2 dopamine and 5HT1A serotonin receptors, and antagonism of the 5HT2 serotonin receptor are believed to be the functional basis of its therapeutic efficacy. Its clinical effects are best documented in patients suffering from schizophrenia and bipolar disorder, in which it has been demonstrated to have antipsychotic and antimanic properties superior to placebo in dose ranges of 10-30 mg/day. Two published longer term trials document maintenance of antipsychotic effects and relapse prevention in schizophrenia patients. In general, aripiprazole seems to be a well-tolerated drug, especially with regard to metabolic side effects. The most commonly reported side effects include restlessness/akathisia, somnolence and nausea. These may be dose-dependent and usually occur early on during treatment, with many patients developing tolerance. Aripiprazole is an interesting and important addition to the currently available spectrum of antipsychotic drugs. Further studies in other indications and clinical trials that confirm results from the Phase II and III clinical development programme are eagerly awaited.
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PMID:Aripiprazole. 1619 61

The changes of P300 parameters (lower amplitude and increased latency) are thought to be the most prominent phenomena of schizophrenia. A role of gene polymorphism in P300 generation was supported by several associative studies in psychiatrically well subjects and patients with mental disorders. We studied P300 parameters and the following polymorphisms: T102C for the serotonin receptor type 2A (5-HTR2A) gene, the 5-HTTLPR for the serotonin transporter gene, -809G/A, -616G/C N -52C/T SNPs in the promoter region of the dopamine D4 receptor (DRD4) gene and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) in 74 patients with schizophrenia and spectrum disorders and 71 their first-degree relatives. No association was found between serotonergic system genes and P300. The -809G/A DRD4 gene polymorphism was related to amplitude in all frontal leads (p=0,01) in patients. In relatives, an association was observed between -521C/T DRD4 variants and latency (p=0,005) as well as between the COMT gene polymorphism and P300 amplitude (p=0,004) at the central lead. Thus, the genes involved in dopaminergic system play a role in P300 generation both in patients with schizophrenia and spectrum disorders and their relatives.
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PMID:[A study of some genes related to serotoninergic and dopaminergic systems and auditory evoked-potentials (P300) in patients with schizophrenia and spectrum disorders and their first-degree relatives]. 1628 77


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