Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Depression with psychotic features has been shown to respond to selective serotonin reuptake inhibitors (SSRIs). The serotonin transporter (5-HTT) is a prime target for SSRIs. A functional polymorphism within the promoter region of the 5-HTT gene, leading to different transcriptional efficiency, was recently reported. We tested the hypothesis that allelic variation of the 5-HTT promoter could be related to the antidepressant response to fluvoxamine and/or augmentation with pindolol (a serotonin autoreceptors antagonist) which has been suggested as an augmentation therapy for nonresponders. One hundred and two inpatients with major depression with psychotic features were randomly assigned to treatment with a fixed dose of fluvoxamine and either placebo or pindolol for 6 weeks. Depression severity was assessed once a week using the Hamilton Depression Rating Scale. Allelic variation in each subject was determined using a PCR-based method. Data were analyzed with a three-way repeated measures analysis of variance. Both homozygotes for the long variant (l/l) of the 5-HTT promoter and heterozygotes (l/s) showed a better response to fluvoxamine than homozygotes for the short variant (s/s). In the group treated with fluvoxamine plus pindolol all the genotypes acted like l/l treated with fluvoxamine alone. Fluvoxamine efficacy in delusional depression seems to be related to allelic variation within the promoter of the 5-HTT gene. Even though other factors may be implicated, genotyping at 5-HTT promoter may represent a promising tool to individualize the pharmacological treatment of depression.
Mol Psychiatry 1998 Nov
PMID:Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. 1082 34

Disturbances of the serotoninergic neutrotransmitter system have been implicated in the pathogenesis of mood disorders. A functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has been recently reported to be associated with both unipolar and bipolar disorder. In this study, we investigated the possibility that the 5-HTTLPR might be associated with depressive symptomatology in a sample of mood disorder subjects. One hundred and thirty-two psychiatric inpatients affected by major depressive (n = 67) and bipolar (n = 65) disorder (DSM-IV) were assessed at admission by the Hamilton Depression Rating Scale (HAMD-21, divided into Core, Sleep, Activity, Psychic anxiety, Somatic anxiety and Delusion clusters) and were typed using PCR techniques. The only prior treatment permitted was low dose benzodiazepines (<5 mg diazepam or equivalent); no prior (<2 weeks) antidepressant or neuroleptic treatment was allowed. 5-HTTLPR variants were not associated with total depressive symptomatology as measured by HAMD. The short 5-HTTLPR variant was marginally associated with higher psychic anxiety scores (F = 7.11, d.f. = 1,262, P = 0.008). The association was stronger among bipolars and early onset subjects. 5-HTTLPR variants were not associated with the remaining symptom clusters. The upstream regulatory region of the serotonin transporter gene has not, therefore, a major influence on the depressive symptomatology in mood disorder subjects.
Mol Psychiatry 1999 May
PMID:Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. 1039 20

Brain dopamine receptor agonists alleviate the signs of Parkinson's disease, while dopamine receptor antagonists alleviate hallucinations and delusions in psychosis. The dopamine type 2 receptor (or D2) is blocked by antipsychotic drugs, including even the "atypical" drugs such as clozapine or remoxipride, in direct relation to their clinical potencies. Compared to the long form of the D2 receptor (D2(Long)), the short form (D2(Short)) may be three times more sensitive to benzamide antipsychotic drugs. Hence, it is essential to identify additional variants of dopamine receptors for which more selective antipsychotic drugs can be found. Although no family linkage has been found between the D2 receptor and schizophrenia, there can be brain region abnormalities in the RNA transcript expression of dopamine receptors. Therefore, in order to identify variant dopamine D2 receptors, we searched for mutations in the RNA transcripts for the dopamine D2 receptor in the striatum of post-mortem brains from individuals who died with psychosis, including schizophrenia. A new splice variant of the D2 receptor, D2(Longer), with a unique TG splice site, was found in one control brain and in two psychotic brains.
Brain Res Mol Brain Res 2000 Mar 10
PMID:New dopamine receptor, D2(Longer), with unique TG splice site, in human brain. 1071 23

The D2 receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder (n = 480), major depressive disorder (n = 269), schizophrenia (n = 366), delusional disorder (n = 44), psychotic disorder not otherwise specified (n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses.
Mol Psychiatry 2000 May
PMID:Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses. 1088 29

The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies as far as mild to moderate depression is involved. However, it seems that some antidepressants are more effective than others in the treatment of severe types of depression (i.e., delusional depression and refractory depression). Following studies regarding the antinociceptive mechanisms of various antidepressants, we speculate that the involvement of the opioid system in the antidepressants' mechanism of action may be necessary, in order to prove effective in the treatment of severe depression. Among the antidepressants of the newer generations, that involvement occurs only with venlafaxine (a presynaptic drug which blocks the synaptosomal uptake of noradrenaline and serotonin and, to a lesser degree, of dopamine) and with mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-auto- and hetero-adrenoreceptors). When mice were tested with a hotplate analgesia meter, both venlafaxine and mirtazapine induced a dose-dependent, naloxone-reversible antinociceptive effect following ip administration. Summing up the various interactions of venlafaxine and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor, whereas the antinociceptive effect of mirtazapine mainly involves mu- and kappa3-opioid mechanisms. This opioid profile of the two drugs may be one of the explanations to their efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity.
J Mol Neurosci
PMID:Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression? 1193 44

Schizophrenia is a severe psychiatric illness characterised by disturbance of thought, hallucination and delusions.(1) Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and in particular an excessive activation of glutamate receptors seems to be related to the disruption of neuronal ionic gradients leading to excitotoxicity.(2-7) Numerous findings suggested that the kainate ionotropic glutamate receptors are primarily involved in this mechanism. Recently it has been demonstrated that the GRIK3 gene encoding for the ionotropic glutamate receptor kainate 3 contains a functional polymorphism (T928G) leading to the substitution of a serine with an alanine in position 310 of the protein sequence.(8-11) We performed an association study between the ser310ala GRIK3polymorphism and schizophrenia in a sample of 99 schizophrenic patients and 116 controls. We found a significant difference in the genotype distribution and in particular considering the ala allele as dominant (P = 0.0105, odds ratio (OR) 2.031, 95% confidence interval (CI) 1.177-3.504). This finding suggests a potential role for GRIK3 for susceptibility to schizophrenia.
Mol Psychiatry 2002
PMID:Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia. 1198 86

Though efforts to identify the genetic etiology of Alzheimer disease (AD) have made substantial progress, to date only some of the genes contributing to AD risk have been identified. Utilization of more etiologically homogeneous subphenotypes represents one strategy to facilitate the identification of novel risk genes in complex disorders. In this review, we evaluate the hypothesis that psychotic symptoms, such as delusions and hallucinations, define a suitable subphenotype in AD patients for gene-mapping efforts. Psychotic symptoms occur in 40-60% of patients with AD and are associated with more severe cognitive deficits and a more rapidly deteriorating course. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings. Candidate gene association analyses and initial linkage analysis have yielded significant results. We discuss possible genetic models of psychotic symptoms in AD, and suggest strategies for further investigation. Identification of such genetic factors may facilitate gene-mapping studies for both AD and idiopathic psychoses.
Mol Psychiatry 2003 Apr
PMID:Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype. 1274 May 95

We have previously reported a linkage peak on 1q42 in a Finnish schizophrenia sample. In this study we genotyped 28 single nucleotide polymorphisms (SNPs) from 1q42 covering the three candidate genes TRAX, DISC1 and DISC2, using a study sample of 458 Finnish families ascertained for schizophrenia. Two-point and haplotype association analysis revealed a significant region of interest within the DISC1 gene. A common haplotype (HEP3) was observed to be significantly under-transmitted to affected individuals (P=0.0031). HEP3 represents a two SNP haplotype spanning from intron 1 to exon 2 of DISC1. This haplotype also displayed sex differences in transmission distortion, the under-transmission being significant only to affected females (P=0.00024). Three other regions of interest were observed in the TRAX and DISC genes. However, analysis of only those families with complete genotype information specifically highlights the HEP3 haplotype as a true observation. The finding of a common under-transmitted SNP haplotype might imply that this particular allele offers some protection from the development of schizophrenia. Analysis of component-traits of schizophrenia, derived from the Operational Criteria Checklist of Psychotic Illness (OCCPI), displayed association of HEP3 to features of the general phenotype of schizophrenia, including traits representing delusions, hallucinations and negative symptoms. This study provides further evidence for the hypothesis that the DISC1 gene is involved in the aetiology of schizophrenia, and implies a putative sex difference for the effect of the gene. Our findings would also encourage more detailed analyses of the effect of DISC1 on the component-traits of schizophrenia.
Hum Mol Genet 2003 Dec 01
PMID:Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. 1453 31

Proper management of chemotoxicity in transplant patients requires detailed knowledge of the biochemical mechanisms underlying immunosuppressant toxicity. Neurotoxicity is one of the most significant clinical side effects of the immunosuppressive undecapeptide cyclosporine, occurring at some degree in up to 60% of transplant patients. The clinical symptoms of cyclosporine-mediated neurotoxicity consist of decreased responsiveness, hallucinations, delusions, seizures, cortical blindness, and stroke-like episodes that mimic those clinical symptoms of mitochondrial encephalopathy. Clinical computed tomography (CT) and magnetic resonance imaging (MRI) studies have revealed a correlation between clinical symptoms of cyclosporine-mediated neurotoxicity and morphological changes in the brain, such as hypodensity of white matter, cerebral edema, metabolic encephalopathy, and hypoxic damages. Paradoxically, in animal models cyclosporine protects the brain from ischemia-reperfusion (I/R) injury. Interestingly, cyclosporine appears to mediate both neurotoxicity (under normoxic conditions) and I/R protection across the same range of drug concentration. Both toxicity and protection might arise from the intersection of cyclosporine with mitochondrial energy metabolism. This review addresses basic biochemical mechanisms of: 1) cyclosporine toxicity in normoxic brain, and 2) its protective effects in the same organ during I/R. The marked and unparallel potential of magnetic resonance spectroscopy (MRS) as a novel quantitative approach to evaluate metabolic drug toxicity is described.
Mol Interv 2004 Apr
PMID:Biochemical mechanisms of cyclosporine neurotoxicity. 1508 83

Dermatologists and psychiatrists occasionally encounter patients who believe they are infested with skin parasites. They may report seeing threads, fibers and more solid appearing particles attached to their skin and hair, or appearing on clean bed sheets after sleeping. Some of the particles move spontaneously suggesting a life form. Similar structures develop in long-term cultures of stealth-adapted viruses. They are termed alternative cellular energy pigments (ACE pigments) since they appear to provide a non-mitochondria source of cellular energy that can assist in cellular repair from the virus cytopathic effect (CPE). Particles obtained from the skin of stealth virus culture-positive patients can also display auto-fluorescence and electrostatic properties. Some of the particles are magnetic and can generate gas in an aqueous solution. They also lead to the production of lipid-like crystals similar to those produced in long-term cultures of stealth-adapted viruses. It is proposed that skin-derived particles that form in some of the patients assumed to be experiencing a delusional parasitosis are, in reality, a reflection of the body's production of ACE pigments.
Exp Mol Pathol 2005 Jun
PMID:Alternative cellular energy pigments mistaken for parasitic skin infestations. 1592 73


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