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)

Compared to conventional antipsychotic medications, atypical antipsychotic medications demonstrate greater central serotonin (5HT2) receptor antagonism than dopamine type 2 (D2) receptor antagonism. Nefazodone, an antidepressant medication, exhibits 5HT2 receptor antagonism; we therefore wondered if its addition to stable regimens of antipsychotic medication would increase antipsychotic efficacy, independently of a primary effect on mood, through the mechanism of augmented 5HT2 receptor antagonism. In a pilot investigation, we administered nefazodone (400 mg/d) for 6 weeks as an open-label adjunct to antipsychotic medication in 10 patients with chronic schizophrenia. The patients were moderately depressed at baseline but did not meet criteria for major depressive episode. The Brief Psychiatric Rating Scale (BPRS) and Montgomery-Asberg Depression Rating Scale scores showed statistically significant and clinically robust improvements with nefazodone treatment, which were maintained at follow-up evaluation 2 weeks after the end of nefazodone treatment. There were no adverse events. These results suggest that nefazodone may be a safe and effective adjunct to antipsychotic medications in schizophrenia and that augmentation of 5HT2 antagonism may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating depressive symptoms in schizophrenia.
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PMID:Nefazodone in the adjunctive therapy of schizophrenia: an open-label exploratory study. 1102 Jan 29

Sensorimotor gating of the startle reflex can be assessed via measures of prepulse inhibition (PPI), which is the reduction in startle magnitude when the startling stimulus is preceded immediately by a weak prepulse. PPI is reduced in humans with specific neuropsychiatric disorders and in rats after treatment with certain classes of drugs, including serotonin (5-HT) agonists. Because of the relative loss of PPI in inherited, neurodevelopmental disorders such as schizophrenia, there is great interest in understanding the inherited and developmental features of the neurochemical regulation of PPI in animals. In the present study, PPI was disrupted significantly by the 5-HT2A agonist 2, 5-dimethoxy-4 iodopheny-lisopropylamine (DOI) in Sprague Dawley (SDH) and Wistar rat strains (WH). While it was demonstrated that the DOI effects in SDH rats reflected an unequivocal disruption of sensorimotor gating, in WH rats, reduced PPI was observed in the context of a trend for a DOI-induced reduction in startle magnitude. This effect of DOI in SDH rats was evident at the earliest date tested (17 days of age) in male pups, but was not statistically significant in female pups. Thus, the regulation of sensorimotor gating by 5-HT2A receptor stimulation in rats may exhibit subtle differences across strains, and within SDH rats, between sexes. Most importantly, the 5-HT2A regulation of sensorimotor gating in male SDH rats is a "phenotype" that is expressed very early in life, and is sustained through adulthood.
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PMID:Regulation of sensorimotor gating of the startle reflex by serotonin 2A receptors. Ontogeny and strain differences. 1106 18

Although population genetic studies have long confirmed the genetic vulnerability of schizophrenia,ongoing advances in molecular genetic technology and biostatistic analysis are only now making it possible to search for the susceptibility gene of the disease. This article reviewed some of the recent findings in this area: (1) The heritability of schizophrenia is estimated around 60%-80%. The phenotype differentiation is based on standard diagnostic scales and symptom rating scales. (2) The two main approaches to finding the genes that influence the disorder are now genomic scan and candidate gene detection. Affected sib-pair (ASP) method and transmission disequilibrium test(TDT) are considered promising analyses. (3) The positive candidate regions with some independent replicable reports concentrated on 6p, 22q and 8p. Positive findings of candidate gene research involved 5-HT2A receptor, DRD3, NT-3, etc. Further directions to identify the susceptibility genes include: Applying more precise instruments to define clinical phenotype of the disease. Application of proper biological markers such as electrophysiologic parameters and brain imaging will be a prospective approach. Using larger sample to increase statistic power and developing more powerful statistic analysis, and performing advanced molecular genetic technique such as DNA pooling, DNA chips, genomic mismatch scanning (GMS), representational difference analysis(RDA), comparative genomic hybridization(CGH) and two-dimensional DNA typing methods will also facilitate this research area to greater perspective.
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PMID:[Progress in the studies on the molecular genetics of schizophrenia]. 1111 Sep 86

The effect of ritanserin on dopamine (DA) re-uptake and efflux was studied in rat frontal cortex synaptosomes. When compared to other 5HT2 receptor antagonists such as ketanserin and risperidone or DA D2 receptor antagonists such as haloperidol and raclopride, the effect of ritanserin proved to be more potent. Ritanserin blocked the DA transporter with a Ki of 0.18 +/- 0.06 microM, similar to cocaine (0.11 +/- 0.005 microM), while ketanserin had a Ki of 0.93 +/- 0.045; haloperidol of 2.07 +/- 0.12; risperidone of 18.01 +/- 0.62 and raclopride of 24.01 +/- 1.55. In addition, 15 min from its local application to the synaptosomes, ritanserin potently released [3]H-DA leaving only 29.6 +/- 1.6% of DA content, while ketanserin effect was equal to 46.5 +/- 0.9%; haloperidol to 70.4 +/- 2.2% and risperidone to 73.9 +/- 1.5%, all tested at the dose of 10 microM. Cocaine had no effect on DA efflux. These results suggest that ritanserin has a intrinsic dopaminergic effect which may help to explain its reported improvement on mood, cognition and negative symptoms of schizophrenia.
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PMID:The 5-HT2 antagonist ritanserin blocks dopamine re-uptake in the rat frontal cortex. 1112 98

1. The pathological process that precipitates schizophrenia has yet to be identified. However, many lines of evidence suggest that a change in the functioning of the frontal cortex is an important abnormality that underlies schizophrenia. 2. Studies in Brodmann's area 9, obtained post-mortem, have shown changes in 5-hydroxytryptamine 5-HT2A, muscarinic M1 and GABA(A) receptors in tissue from subjects with schizophrenia. 3. Animal studies suggest a site in the cortex where there would be an interaction between serotonergic and cholinergic innervation and that this interaction would involve the 5-HT2A and the M1 receptor. This site, in turn, would be a potent modulator of GABA activity and, hence, levels of GABA(A) receptors. 4. From combining these data, a theoretical site is proposed that, if proven to exist in human cortex, is likely to be central to the pathology of that illness.
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PMID:A predicted cortical serotonergic/cholinergic/GABAergic interface as a site of pathology in schizophrenia. 1115 42

The affinity of clozapine for 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, and 5-HT1A receptors has been suggested to contribute to various aspects of its complex clinical actions. This study examined the hypothesis that genetic variation in 5-HT1A, 5-HT6, and 5-HT7 receptor genes is involved in the variability observed in response to clozapine. We employed a pharmacogenetic approach in a group (n=185) of schizophrenia patients that have been clinically well characterized for clozapine response. Polymorphisms in the 5-HT6 (HTR6), 5-HT1A (HTR1A) and 5-HT7 (HTR7) receptor genes were genotyped. No evidence for either an allelic or genotypic association of the T-->C 267 HTR6 polymorphism with response to clozapine was found in our sample (allele: chi(2)=0.06, 1 df, P=0.80; genotype: chi(2)=1.21, 2 df, P=0.55). The pro16leu HTR1A polymorphism was not observed in our sample; all individuals genotyped were pro/pro 16 homozygotes. With respect to the pro279leu HTR7 polymorphism, one Caucasian male responder to clozapine was observed to be heterozygous (pro/leu 279 genotype). This individual was clinically similar to the other clozapine responders. Overall, our findings do not support a role for the T-->C 267 polymorphism of the 5-HT6 receptor gene in response to clozapine, although replication is required to confirm this finding.
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PMID:Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. 1116 44

The administration of the N-methyl-D-aspartate (NMDA)-associated glycine recognition site agonist D-cycloserine (DCS) to rats inhibited the head shakes and the forepaw treading induced by the serotonin (5HT) precursor, L-5-hydroxy-tryptophan [(-)5HTP], as well as the forepaw treading and motility elicited by the selective 5HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The head shakes typically induced by the 5HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), were unaffected by DCS pretreatment. The results are consistent with reduced serotonergic transmission produced by NMDA activation, as suggested by other authors. Due to the important role played in the pathogenesis of schizophrenia by glutamate deficiency/serotonin activation, the results support the view that positive modulators of NMDA receptors, activating glutamate receptors and reducing serotonergic tone, might be useful in the alleviation of psychotic symptoms. However, because of its partial agonist properties at the glycine recognition site, D-cycloserine shows some effects that might make it unsuitable for clinical use.
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PMID:D-Cycloserine, a positive modulator of NMDA receptors, inhibits serotonergic function. 1119 34

The last ten years have witnessed the generation of a large amount of information on the neurobiology of dopamine receptors. Molecular biology and pharmacology studies have revealed existence of at least five dopamine receptor subtypes, namely D1, D2, D3, D4 and D5. The discovery of D4 receptors and the putative affinity of clozapine for D4 receptors have kindled development of selective D4 receptor antagonists for the treatment of schizophrenia. Studies on expression of D4 receptor proteins have shown selective localisation of D4 receptors in mesolimbic/mesocortical areas which could probably explain the lack of motor side effects with atypical antipsychotics like clozapine and olanzapine. However, neuropathological and genetic studies on the role of D4 receptors in the pathophysiology of schizophrenia and preliminary clinical studies with selective D4 receptor antagonists have been disappointing. There have been, however, complimentary findings between selective D4 receptor antagonism and genetic approaches such as antisense treatment or gene targeting. The therapeutic potential of D4 receptors as a target for developing antipsychotics will be known only when selective D4 receptor-antagonists with varying D2/D4 and D4/5-HT2A ratios are developed and tested in psychiatric patients.
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PMID:Dopamine D4 receptors and development of newer antipsychotic drugs. 1120 2

The atypical antipsychotics have advanced the treatment of schizophrenia and have proved to be effective agents in treating other disorders with or without psychotic features. We review the literature concerning an increasingly reported and interesting adverse effect, atypical antipsychotic-induced obsessive-compulsive symptoms (OCS). The first known report of quetiapine exacerbating OCS in a 43-year-old man with obsessive-compulsive disorder (OCD), trichotillomania, delusional disorder and bipolar II disorder is presented. Mechanisms, including 5-HT2A and 5-HT2C antagonism, serotonergic regulation of dopamine systems and putative dopaminergic subtypes of OCS and OCD, are discussed. Given the paradoxical efficacy of the atypical antipsychotics in pure OCD, the neurobiology and comorbidity of OCD and schizophrenia, as well as the increasing use of atypical antipsychotics, a cautious and rational pharmacotherapeutic treatment approach is recommended.
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PMID:Quetiapine and obsessive-compulsive symptoms (OCS): case report and review of atypical antipsychotic-induced OCS. 1121 95

The negative symptoms of schizophrenia remain a major clinical challenge. Mirtazapine is an antidepressant with antagonist properties at 5-HT2A, 5-HT3 and alpha 2 receptors as well as indirect 5-HT1a agonist effects. Many of these pharmacological actions have clinical or preclinical evidence of efficacy in schizophrenia. This study was a 6-week randomized placebo-controlled trial of mirtzepine or placebo add on to haloperidol 5 mg in the treatment of 30 patients with DSM-IV schizophrenia. The primary finding of the trial was a 42% reduction in Positive and Negative Syndrome Scale (PANSS) negative symptom scores in the mirtazapine group compared to placebo at the end of 6 weeks (mirtazapine 13.9, SD 1.56; placebo 23.9, SD 1.56; P = 0.000, F = 20.31, d.f. = 1). The PANNS total scores, Clinical Global Impression severity and improvement scales in addition showed superiority of mirtazapine over placebo. There was no difference between the groups on the Hamilton depression scale at endpoint, suggesting that the improvement in negative symptoms was not an artifact of mood improvement. These results suggest a potential role for mirtazapine in the negative symptoms of schizophrenia.
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PMID:Efficacy of mirtazapine add on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. 1123 73


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