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 neurologic processes involved in schizophrenia are complex and diverse and the mechanisms through which antipsychotic agents exert their effects have been only partly elucidated. Hyperprolactinemia is a common side effect of treatment with many antipsychotics and is particularly associated with conventional ('typical') agents as well as the atypical antipsychotic risperidone. In contrast, other atypical agents introduced over the last decade do not elevate prolactin levels. This article discusses the regulatory mechanisms involved in prolactin secretion, the physiologic role of prolactin, and the etiology of hyperprolactinemia. Elevated prolactin levels may play important roles, both direct and indirect, in various pathologic states, including breast cancer, osteoporosis, cardiovascular disorders, and sexual disturbances. Antipsychotic-induced hyperprolactinemia may be associated with similar clinical manifestations; these are examined with particular reference to patients with schizophrenia.
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PMID:Elevated prolactin levels in patients with schizophrenia: mechanisms and related adverse effects. 1250 72

The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. The neuregulin family of genes has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins, and they are considered in this review only briefly. The NRG1 proteins play essential roles in the nervous system, heart, and breast. There is also evidence for involvement of NRG signaling in the development and function of several other organ systems, and in human disease, including the pathogenesis of schizophrenia and breast cancer. There are many NRG1 isoforms, raising the question "Why so many neuregulins?" Study of mice with targeted mutations ("knockout mice") has demonstrated that isoforms differing in their N-terminal region or in their epidermal growth factor (EGF)-like domain differ in their in vivo functions. These differences in function might arise because of differences in expression pattern or might reflect differences in intrinsic biological characteristics. While differences in expression pattern certainly contribute to the observed differences in in vivo functions, there are also marked differences in intrinsic characteristics that may tailor isoforms for specific signaling requirements, a theme that will be emphasized in this review.
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PMID:Neuregulins: functions, forms, and signaling strategies. 1264 63

The authors investigated the risk for breast cancer in schizophrenia in a cohort of 1336313 Danish women born after 1935, including information on reproductive factors. In all, 7541 had been hospitalized for schizophrenia in 1970-1997 and the overall relative risk for breast cancer adjusted for age, period, age at first birth and number of births was not increased (RR, 0.91; 95% confidence interval, 0.71-1.12). Studies not taking parity into account may overestimate the risk for breast cancer in schizophrenic women.
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PMID:Schizophrenia and the risk for breast cancer. 1276 48

Dehydroepiandrosterone is the most abundant adrenal androgen and also functions as a neurosteroid. Serum concentrations decline with age and can serve as a prognostic factor in both critical illnesses and breast cancer progression. Evidence is accruing in support of dehydroepiandrosterone supplementation in adrenal insufficiency, hypopituitarism, osteoporosis, systemic lupus erythematosus, depression and schizophrenia. Research is ongoing at both the basic and the clinical level to elucidate mechanisms of action and establish efficacy and safety, as well as to expand new areas of potential application for this multi-faceted hormone.
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PMID:Clinical uses and misuses of dehydroepiandrosterone. 1464 16

Cancer might be expected to be more common amongst schizophrenics than the general population. They frequently live in selenium deficient regions, have seriously compromised antioxidant defense systems and chain-smoke. The available literature on the cancer-schizoprenia relationship in patients from England, Wales, Ireland, Denmark, USA and Japan, however, strongly suggests that the reverse is true. One of the authors (Hoffer) has treated 4000 schizophrenics since 1952. Only four of these patients has developed cancer. Since low cancer incidence has been recorded amongst patients treated by both conventional physicians using pharmaceuticals and by orthomolecular doctors who emphasize vitamins and minerals, it follows that this depressed cancer incidence must be related to the biochemistry of the disorder itself. Taken as a whole, therefore, the evidence seems to suggest that schizophrenics, their siblings and parents are less susceptible to cancer than the general population. These relationships seem compatible with one or more genetic risk factors for schizophrenia that offer(s) a selective advantage against cancer. There is experimental evidence that appears to support this possibility. Matrix Pharmaceuticals Inc. has received a US patent covering the composition of IntraDose Injectable Gel. This gel contains cisplatin and epinephrine (adrenaline) and is designed to be injected directly into tumour masses. Cisplatin is a very powerful oxidant which will almost certainly rapidly convert the adrenaline to adrenochrome. While the manufacturers of IntraDose consider cisplatin to be the active cytotoxic agent in IntraDose, it seems more likely that adrenochrome and its derivatives may, in fact, be more effective. IntraDose gel has undergone or is undergoing a series of Phase III open-label clinical studies, being injected into patients' tumours that have been identified as the most troublesome by their physicians. The results have been impressive for breast cancer, malignant melanoma, esophageal cancer and cancer of the head, neck and liver. The evidence suggests that there are balanced morphisms in schizophrenia that result in above normal exposure to catecholamine derivatives. Since such catecholamines are both hallucinogenic and anticarcinogenic abnormally high exposure to them simultaneously increases susceptibility to schizophrenia and reduces the probability of developing cancer. These observations have significant implications for the treatment of both illnesses.
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PMID:Schizophrenia and cancer: the adrenochrome balanced morphism. 1497 14

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.
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PMID:The DNA sequence and analysis of human chromosome 13. 1505 23

Evidence that the quality of fetal growth and development has strong and, in widely varying populations, reproducible effects on susceptibility to many common adult human diseases has only been acquired relatively recently. The importance of this largely environmentally determined process in relation to genetic factors remains a topic of great debate. Diseases that have been implicated include cardiovascular disease, hypertension, osteoporosis, schizophrenia, depression, breast cancer, and the polycystic ovary syndrome. This short review focuses on fetal programming of appetite and obesity, coronary artery disease and hypertension, type-2 diabetes, and cancer. The enormous importance of establishing the precise role of environmentally determined poor fetal growth in causing susceptibility to adult disease, usually in combination with adult obesity, (which may itself be a consequence of the same process) is emphasized. Once this is clear, there will be a major opportunity for disease prevention.
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PMID:Fetal growth and adult diseases. 1505 5

Hyperprolactinaemia is an important but neglected adverse effect of antipsychotic medication. It occurs frequently with conventional antipsychotics and some atypical antipsychotics (risperidone and amisulpride) but is rare with other atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, ziprasidone). For this reason the terms 'prolactin-sparing' and 'prolactin-raising' are more useful than 'atypical' and 'conventional' when considering the effect of antipsychotic drugs on serum prolactin. During antipsychotic treatment prolactin levels can rise 10-fold or more above pretreatment values. In a recent study approximately 60% of women and 40% of men treated with a prolactin-raising antipsychotic had a prolactin level above the upper limit of the normal range. The distinction between asymptomatic and symptomatic hyperprolactinaemia is important but is often not made in the literature. Some symptoms of hyperprolactinaemia result from a direct effect of prolactin on target tissues but others result from hypogonadism caused by prolactin disrupting the normal functioning of the hypothalamic-pituitary-gonadal axis. Symptoms of hyperprolactinaemia include gynaecomastia, galactorrhoea, sexual dysfunction, infertility, oligomenorrhoea and amenorrhoea. These symptoms are little researched in psychiatric patients. Existing data suggest that they are common but that clinicians underestimate their prevalence. For example, well conducted studies of women treated with conventional antipsychotics have reported prevalence rates of approximately 45% for oligomenorrhoea/amenorrhoea and 19% for galactorrhoea. An illness-related under-function of the hypothalamic-pituitary-gonadal axis in female patients with schizophrenia may also contribute to menstrual irregularities. Long-term consequences of antipsychotic-related hypogonadism require further research but are likely and include premature bone loss in men and women. There are conflicting data on whether hyperprolactinaemia is associated with an increased risk of breast cancer in women. In patients prescribed antipsychotics who have biochemically confirmed hyperprolactinaemia it is important to exclude other causes of prolactin elevation, in particular tumours in the hypothalamic-pituitary area. If a patient has been amenorrhoeic for 1 year or more, investigations should include bone mineral density measurements. Management should be tailored to the individual patient. Options include reducing the dose of the antipsychotic, switching to a prolactin-sparing agent, prescribing a dopamine receptor agonist and prescribing estrogen replacement in hypoestrogenic female patients. The efficacy and risks of the last two treatment options have not been systematically examined. Antipsychotic-induced hyperprolactinaemia should become a focus of interest in the drug treatment of psychiatric patients, particularly given the recent introduction of prolactin-sparing antipsychotics. Appropriate investigations and effective management should reduce the burden of adverse effects and prevent long-term consequences.
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PMID:Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. 1545 28

We investigated the cancer risk of patients hospitalized for schizophrenia in a nationwide cohort study. All 22766 adults admitted for schizophrenia, ICD-8 295, in Denmark between 1969 and 1993 were followed up for cancer through 1995. The incidence of site-specific cancers was compared with national incidence rates, adjusted for sex, age and calendar time. The risk for cancer was increased for both men and women during the first year of follow-up. When the first year of follow-up was excluded, the risk for all tobacco-associated cancers and for prostate and rectal cancers was reduced for male patients with schizophrenia. The standardized incidence ratio (SIR) of lung cancer was marginally reduced (SIR, 0.86; 95% CI: 0.65, 1.02) for male patients with schizophrenia; this was due, however, to a reduction in risk for older patients. An increased risk for breast cancer found for female patients with schizophrenia (SIR, 1.20; 95% CI: 1.05, 1.38) should be interpreted with caution, given the high proportion of nulliparous women with schizophrenia in Denmark. The data might support reduced risks for prostate and rectal cancer among male patients with schizophrenia, whereas a changing smoking pattern might explain the reduced risk for tobacco-related cancers.
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PMID:Risk for cancer in a cohort of patients hospitalized for schizophrenia in Denmark, 1969-1993. 1588 23

The human gene for catechol O-methyltransferase (COMT) contains a common polymorphism that results in substitution of methionine (M) for valine (V) at residue 108 of the soluble form of the protein. While the two proteins have similar kinetic properties, 108M COMT loses activity more rapidly than 108V COMT at 37 degrees C. The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 degrees C. The 108M allele has been associated with increased risk for breast cancer, obsessive-compulsive disorder, and aggressive and highly antisocial manifestations of schizophrenia. In the current work, we have constructed homology models for both human COMT polymorphs and performed molecular dynamics simulations of these models at 25, 37, and 50 degrees C to explore the structural consequences of the 108V/M polymorphism. The simulations indicated that replacing valine with the larger methionine residue led to greater solvent exposure of residue 108 and heightened packing interactions between M108 and helices alpha2, alpha4 (especially with R78), and alpha5. These altered packing interactions propagated subtle changes between the polymorphic site and the active site 16 A away, leading to a loosening of the active site. At physiological temperature, 108M COMT sampled a larger distribution of conformations than 108V. 108M COMT was more prone to active-site distortion and had greater overall, and SAM binding site, solvent accessibility than 108V COMT at 37 degrees C. Similar structural perturbations were observed in the 108V protein only at 50 degrees C. Addition of SAM tightened up the cosubstrate pocket in both proteins and prevented the altered packing at the polymorphic site in 108M COMT.
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PMID:The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures. 1647 6


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