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)

A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using [123I]iodobenzamide (IBZM) SPECT. The occupancy of DA D2 receptors was not significantly different between olanzapine and risperidone. However, in subgroups of most prescribed doses, DA D2 occupancy was higher in the risperidone 4-mg group (79%) compared to the olanzapine 15-mg group (62%). [123I]IBZM binding ratios decreased with olanzapine dose (r = -0.551; P < 0.01), indicating higher DA D2 receptor occupancy with higher olanzapine dose. Akathisia and positive symptoms were correlated with [123I]IBZM binding ratio (r = -0.442; P < 0.01; and r = -0.360; P < 0.05, respectively). Prolactin (PRL) levels were elevated in the risperidone, but not in the olanzapine group, at comparable D2 receptor occupancy levels. In the olanzapine group, PRL levels were correlated with [123I]IBZM binding ratio (r = -0.551; P < 0.01). In conclusion, both olanzapine and risperidone induce a high striatal D2 receptor occupancy, dependent on dose and group formation. The lower incidence of prolactin elevation with olanzapine, compared to risperidone, may not be attributed to a lower D2 receptor occupancy.
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PMID:Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia. 1068 58

The administration of dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist acting at the associated ion channel, increased the grooming time induced in rats by the D1 dopamine receptor agonist SKF 38393 and the stereotyped behaviour elicited by the D1/D2 dopamine receptor agonist apomorphine, and reduced the locomotor response to the D2 dopamine receptor agonist quinpirole. This supports the view that glutamate deficiency plays an important role in the pathogenesis of schizophrenia by altering the balance between glutamatergic and dopaminergic systems. Blockade of serotonin receptors counteracted the effect of dizocilpine on dopaminergic responses. Both the non-selective 5HT1/5HT2 antagonist methysergide, and ketanserin, which more specifically blocks 5HT2 receptors, given at doses inhibiting serotonin-mediated behaviours but which did not affect spontaneous motility and dopaminergic behaviours, hampered the dizocilpine-induced potentiation of responses elicited by the stimulation of D1 or D1/D2 dopamine receptors and counteracted the dizocilpine-induced reduction of hyperactivity observed following quinpirole administration. The results suggest that the functional integrity of the serotonergic system is fundamental for the occurrence of dopaminergic changes resulting from non-competitive NMDA blockade.
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PMID:Blockade of the serotonergic system counteracts the dizocilpine-induced changes in dopaminergic function. 1082 Dec 6

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

The TaqIA D2 dopamine receptor (DRD2) minor (A1) allele was first associated with severe alcoholism a decade ago. Since then, studies both confirming and not confirmnning this finding were reported. However, a meta-analysis of a large number of Caucasian alcoholics (both more severe and less severe) and controls (both assessed and unassessed for substance use disorders) revealed a significantly higher frequency (p < 10(-6)) and prevalence (p < 10(-8)) of the DRD2 A1 allele in the alcoholics. Further analysis showed that the more severe alcoholics had a 3-fold higher prevalence of the DRD2 A1 allele than the assessed controls (p < 10(-10)), whereas no difference was found between the less severe alcoholics and the unassessed controls. DRD2 exonic or promoter mutations have not yet been associated with alcoholism, although two intronic variants at the TaqIB and intron 6 sites, which are in linkage disequilibrium with the TaqIA site, were associated with this disorder. Variants of the DRD2 gene have also been associated with cocaine, nicotine and opioid dependence, obesity and gambling. It is hypothesised that the DRD2 is a reinforcement or reward gene. Although less intensively studied than substance use disorders, the DRD2 gene has been implicated in Tourette's syndrome (TS), post-traumatic stress disorder (PTSD) and certain symptoms associated with affective disorders and schizophrenia. Further, DRD2 variants have been implicated in Parkinson's disease (PD) and in iatrogenically-induced movement disorders, as well as in certain migraineurs. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in the brain of subjects who carry the DRD2 A1 allele. In addition, phenotypic differences have been found in neurocognitive and personality characteristics, and in treatment outcome of DRD2 variants. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the prevention and treatment of these disorders.
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PMID:The DRD2 gene in psychiatric and neurological disorders and its phenotypes. 1125 81

The aim of this study was to compare in vivo striatal D2 dopamine receptor occupancy induced by olanzapine and haloperidol in schizophrenic patients using a baseline-endpoint [(123)I]IBZM single photon computed emission tomography (SPECT) design. The relationships of striatal D2 receptor occupancy with clinical efficacy and extrapyramidal symptoms (EPS) were also assessed. Twenty-seven inpatients with schizophrenia or schizophreniform disorder were included in a 4-week prospective, randomized, double-blind, parallel and comparative clinical trial. Thirteen patients were treated with haloperidol (10 mg/day) and 14 with olanzapine (10 mg/day). Ratings of clinical status and EPS were obtained weekly. The percentage of D2 receptor occupancy was estimated by using basal ganglia (striatum)/frontal cortex IBZM uptake ratios obtained from each patient before and after 4 weeks of maintained antipsychotic treatment. Olanzapine led to a mean striatal D2 receptor occupancy of 49% (range 28-69%), which was significantly lower than that induced by haloperidol (mean 64%, range 46-90%). The baseline-endpoint SPECT design used in this study revealed lower antipsychotic D2 occupancy percentage values than those reported in the literature, using other approaches. The degree of striatal D2 receptor occupancy correlated to the EPS, which predominantly appeared in patients on haloperidol. No relationship was found between the striatal D2 receptor occupancy and clinical improvement. Olanzapine induced a lower striatal D2 occupancy than haloperidol. This low striatal D2 occupancy, together with the lower incidence of EPS in olanzapine-treated patients, contributed to confirm the atypical behavior of this new antipsychotic drug. Nevertheless, conclusions based on SPECT-estimated percentages of antipsychotic D2 occupancy should be cautious, since the SPECT design could influence the results. In this regard, SPECT studies including baseline and endpoint examinations should be encouraged.
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PMID:Double-blind olanzapine vs. haloperidol D2 dopamine receptor blockade in schizophrenic patients: a baseline-endpoint. 1153 Feb 75

The dopamine system is known to be closely involved in brain neuronal dysfunction and in diseases such as Parkinson's disease, Tourette's syndrome, attention deficit hyperactive disorder, generation of pituitary tumors and schizophrenia. According to the classical dopamine hypothesis on the pathology of schizophrenia, conventional antipsychotics has D2 dopamine receptor antagonistic profiles. However, the use of typical antipsychotics has several limitations; that is, some patients do not respond to them, they can even worsen negative symptoms, and they can provoke unacceptable extrapyramidal and endocrine side effects. To produce effective antipsychotics with reduced side effects, partial agonists to D2 dopamine receptors (D2 receptors) have been developed. Despite the effectiveness of partial agonists for pre- and postsynaptic D2 receptors, administration of such drugs results in inconsistent clinical effects to ameliorate the symptoms of schizophrenia. Thus, strategies for obtaining ideal effective antipsychotics with reduced side effects are considered in this short review with respect to the intrinsic efficacies and affinities of the partial agonists, based on the partial agonist concept.
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PMID:Strategy for modulation of central dopamine transmission based on the partial agonist concept in schizophrenia therapy. 1156 10

Controversy surrounds the question of whether there are dopamine (DA) receptor abnormalities in the brains of schizophrenia patients; in particular, whether DA receptors of the D2 family are elevated in density. Methodological factors and sample characteristics have been postulated to account for differences in study outcome, but there has been no systematic analysis of the contribution of these factors to study effect sizes. This meta-analysis of the research findings sought to determine the influence of methodologic factors and sample characteristics on the magnitude of diagnostic group differences in DA D2 density (Bmax) and affinity (Kd). The analysis suggests at least moderate effects, such that schizophrenia patients show an elevation in both values when compared to controls. These effects are amplified in medicated patients, but not solely attributable to antipsychotics. The group differences in DA D2 receptor density and affinity increase with age among nonmedicated patients. The use of a butyrophenone ligand also yields larger effects. It is concluded that a subgroup of schizophrenia patients manifests increased DA D2 receptor density and decreased receptor affinity. In the absence of medication, these changes may become more pronounced with age. Differences in study outcome are also partially due to methodologic factors, including the ligand.
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PMID:Dopamine receptors in the brains of schizophrenia patients: a meta-analysis of the findings. 1171 Jul 51

Understanding the action of atypical antipsychotics is useful in exploring the pathophysiology of schizophrenia and in synthesizing drugs that improve various domains of psychopathology without unwanted side effects. In animal models, atypical antipsychotic drugs appear to have a preferential action in the limbic dopaminergic system. Regionally specific action has been studied by measuring the amount of Fos protein produced in a particular brain region as a consequence of a drug's effects on the c-fos gene. Evidence suggests that the atypical and typical antipsychotic drug-induced increases in Fos levels in the nucleus accumbens are related to improvements in positive symptoms, whereas Fos increases in the prefrontal cortex, with the atypical antipsychotics only, correlate with negative symptom improvement. The extrapyramidal effects seen with typical antipsychotics are thought to be related to Fos increases in the striatonigral pathway. However, studies of Fos levels in specific brain regions reveal only the site of action, not the mode of action. The finding that atypicality is related to surmountable D2 dopamine receptor blocking provides another venue to define and explore atypical antipsychotic drug action.
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PMID:How do the atypical antipsychotics work? 1176 6

The delineation of dopamine dysfunction in the mentally ill has been a long-standing quest of biological psychiatry. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients. We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar cases from the Stanley Foundation Neuropathology Consortium display significantly elevated levels of the D2 dopamine receptor desensitization regulatory protein, neuronal calcium sensor-1. These levels of neuronal calcium sensor-1 were not influenced by age, gender, hemisphere, cause of death, postmortem period, alcohol consumption, or antipsychotic and mood stabilizing medications. The present study supports the hypothesis that schizophrenia and bipolar disorder may be associated with abnormalities in dopamine receptor-interacting proteins.
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PMID:Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients. 1249 48

The D2 dopamine receptor (DRD2) has been one of the most extensively investigated gene in neuropsychiatric disorders. After the first association of the TaqI A DRD2 minor (A1) allele with severe alcoholism in 1990, a large number of international studies have followed. A meta-analysis of these studies of Caucasians showed a significantly higher DRD2 A1 allelic frequency and prevalence in alcoholics when compared to controls. Variants of the DRD2 gene have also been associated with other addictive disorders including cocaine, nicotine and opioid dependence and obesity. It is hypothesized that the DRD2 is a reinforcement or reward gene. The DRD2 gene has also been implicated in schizophrenia, posttraumatic stress disorder, movement disorders and migraine. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in brains of subjects who carry the DRD2 A1 allele. In addition, pleiotropic effects of DRD2 variants have been observed in neurophysiologic, neuropsychologic, stress response, personality and treatment outcome characteristics. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the treatment of these disorders.
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PMID:D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. 1249 24


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