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)

Risperidone and ocaperidone are new benzisoxazol antipsychotics with particularly beneficial effects in schizophrenia. We report a comprehensive study on the in vitro and in vivo receptor binding profile of the new compounds, compared with haloperidol, and on the drug effects on monoamine and metabolite levels in various brain areas. The in vitro receptor binding and monoamine uptake inhibition profiles, comprising 29 receptors and four monoamine uptake systems, revealed that ocaperidone and risperidone bound primarily, and with the highest affinity thus far reported, to serotonin 5HT2 receptors (Ki values of 0.14 and 0.12 nM, respectively). Further, the drugs bound at nanomolar concentrations to the following receptors (Ki values, in nM, for ocaperidone and risperidone, respectively): alpha 1-adrenergic (0.46 and 0.81), dopamine D2 (0.75 and 3.0), histamine H1 (1.6 and 2.1), and alpha 2-adrenergic (5.4 and 7.3). In contrast, haloperidol showed nanomolar affinity for D2 receptors (1.55) and haloperidol-sensitive sigma sites (0.84) only. The in vitro binding affinity of ocaperidone, risperidone, and haloperidol for D2 receptors was exactly the same when measured in membranes from rat striatum, nucleus accumbens, tuberculum olfactorium, and human kidney cells expressing the cloned human D2 receptor (long form). In vivo binding in rats, using intravenous administration of [3H]spiperone, revealed very potent occupation by ocaperidone and risperidone of 5HT2 receptors in the frontal cortex (ED50 of 0.04-0.03 mg/kg); in this respect, they were 6, 30, and 100 times more potent than ritanserin, haloperidol, and clozapine, respectively. Ocaperidone occupied D2 receptors in the striatum and the nucleus accumbens with similar potency as did haloperidol (ED50 of 0.14-0.16 mg/kg). Risperidone revealed biphasic inhibition curves in the latter brain areas, indicating that [3H] spiperone labeled both 5HT2 receptors (occupied by risperidone at less than 0.04 mg/kg) and D2 receptors (risperidone ED50 of approximately 1 mg/kg). In the tuberculum olfactorium, 5HT2 and D2 receptors were also distinguished with risperidone. The ED50 values for occupation of the latter were for ocaperidone and risperidone 2 times lower and for haloperidol 2 times higher than in the striatum. Ocaperidone, risperidone, and haloperidol readily increased the levels of the dopamine metabolites 3,4-dihydroxybenzene acetic acid and homovanillic acid in the striatum, the nucleus accumbens, the tuberculum olfactorium, and, to some extent, the frontal cortex. Dose-response curve shapes were markedly different; with ocaperidone maximal levels were reached at 0.16 mg/kg and maintained to 10 mg/kg; with risperidone the levels tended to increase continuously up to 10 mg/kg. Haloperidol produced dome-shaped curves (maximum at 0.16-0.63 mg/kg).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone. 137 84

Sixty-one adult psychotic patients were treated for four weeks in an open dose-finding study with the new combined serotonin-dopamine antagonist risperidone (R 64 766). Risperidone had a rapid onset of action; a highly significant decrease in the total score on the Brief Psychiatric Rating Scale (BPRS) was already noticed after the first week of treatment. There was also a significant decrease in score for individual BPRS items related to positive, negative, and affective symptoms. In spite of the withdrawal of antiparkinson medication at selection, a significant decrease in extra-pyramidal symptoms (EPS) was observed, as assessed on the Simpson and Angus Scale. The Clinical Global Impression of therapeutic effect was consistent with the BPRS scores, showing a constant improvement throughout the study. The mean daily dose of risperidone at the end of the study was 3.7 mg. Tolerance was excellent and only mild side-effects were reported. Vital signs, ECG-parameters, and laboratory values remained within normal limits. This study demonstrates that risperidone has great potential as an effective and well-tolerated alternative for the treatment of chronically psychotic patients. It has potent antipsychotic effects, a low EPS-inducing profile, and, at the same time, it improves the negative and affective symptoms of schizophrenia.
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PMID:Pilot clinical investigation of risperidone in the treatment of psychotic patients. 170 Dec 62

Comparative studies of the benzisoxazole derivative risperidone (R 64 766) were made with ritanserin, a selective centrally acting serotonin-S2 antagonist and with haloperidol, a selective centrally acting dopamine-D2 antagonist. Risperidone like ritanserin shows activity in all tests related to serotonin-S2 antagonism, but at even lower doses (peripheral S2-antagonism at 0.0011 mg/kg, central S2-antagonism at 0.014 mg/kg). Like haloperidol, risperidone shows activity in all tests related to dopamine-D2 antagonism; activity in rats for both compounds starts at 0.016 mg/kg, but some central nervous system controlled functions, including the induction of catalepsy, are relatively much less affected by risperidone. Qualitatively, risperidone is a mixed serotonin-dopamine antagonist. Quantitatively, its study in dogs reveals potent dopamine-D2 antagonistic activity with excellent p.o. bioavailability and a relatively long duration of action. From the obtained pharmacological data, risperidone could be expected to possess the complementary clinical effects of a ritanserin-like serotonin-S2 and an haloperidol-like dopamine-D2 antagonist. Serotonin-S2 antagonism may improve the quality of sleep, reduce negative and affective symptoms in schizophrenic patients and decrease extrapyramidal symptoms induced by classical neuroleptics. Because risperidone is a dopamine-D2 antagonist, antidelusional, antihallucinatory and antimanic actions are expected. The first clinical studies indicate that two additional therapeutic targets, which are not reached with classical neuroleptics, may be obtained with risperidone in the monotherapy of schizophrenia and related disorders: very important contact and mood-elevating properties and extrapyramidal symptoms-free maintenance therapy.
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PMID:Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. 245 Feb

Risperidone was studied in a 0.16 mg/kg LSD-saline drug discrimination test procedure. At doses varying from 0.0025 to 0.63 mg/kg, no LSD-like agonist effects were observed. Studies on the antagonism of the LSD-cue indicated that risperidone was able to completely block the discriminative stimulus properties of LSD with a minimum ED50-value of 0.028 mg/kg. Risperidone was also very active over time with reference to LSD antagonism, the ED50S after 2, 4 and 8 h pretreatment being 0.028, 0.064 and 0.44 mg/kg. Response rate reductions were only observed at doses greater than or equal to 0.16 mg/kg after 1 h and at 0.63 mg/kg after 2 h pretreatment. Four and 8 h after treatment, no rate-reducing effects were apparent at doses up to 2.50 mg/kg. Thus at pretreatment intervals ranging between 2 and 8 h, complete antagonism of LSD without any rate effects was obtained. As compared to other LSD antagonists, risperidone was quantitatively better than setoperone and ritanserin and longer acting than pirenperone. Based on the pharmacological profile of risperidone and the other LSD antagonists, it was concluded that a potent central 5-HT2 and catecholamine antagonism is needed for a potent and complete antagonism of the 0.16 mg/kg LSD-cue. The potential clinical effect of risperidone in the positive and negative symptoms of schizophrenia is discussed.
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PMID:Risperidone (R 64 766), a potent and complete LSD antagonist in drug discrimination by rats. 247 Dec 20

After a wash-out period of 1 week, 20 patients suffering from schizophrenia were treated for 4 weeks in an open dose-finding study with a new serotonin-dopamine antagonist risperidone. All patients completed the trial. The mean daily dose of risperidone was 4.6 mg (range 2-10 mg) at completion. Risperiodone had a rapid onset of action: a highly significant decrease of the total BPRS score (Brief Psychiatric Rating Scale) was already noticed at the end of the second week. This decrease was found in all BPRS factors after 4 weeks. In spite of the withdrawal of antiparkinson medication at selection, a clear decrease of EPS (extrapyramidal symptoms), assessed on the Simpson and Angus Scale, was observed. The Global Therapeutic Impression agreed to the BPRS scores, showing a highly significant improvement after 2 weeks of treatment. Risperidone was very well tolerated, only mild side effects were reported. Vital signs, electrocardiographic parameters and laboratory values remained normal during the trial. This study indicates that risperidone can be an effective and well-tolerated alternative in the treatment of chronic schizophrenia, combining an antipsychotic activity, a beneficial effect on anergia and anxiety depression and a low EPS-inducing profile.
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PMID:The efficacy of the D2 and 5-HT2 antagonist risperidone (R 64,766) in the treatment of chronic psychosis. An open dose-finding study. 248 25

The pharmacodynamics and pharmacokinetics of risperidone, an important atypical antipsychotic drug with potent serotonin-5-HT2 and dopamine-D2 receptor blocking effects, are presented. The pharmacology of atypical versus typical antipsychotic drugs is discussed in the contest of a pathophysiological conceptualization for schizophrenia which incorporates a parkinsonian model with an important role for serotonin and excitatory amino acid neurotransmission. In the normal therapeutic dose range, risperidone displays dose-linear pharmacokinetics in humans and reaches steady-state within 24 hours. Risperidone metabolism yields a active metabolite, 9-OH-risperidone, that has a similar pharmacological profile to the patient compound and therefore contributes to the clinical efficacy of the drug.
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PMID:Pharmacological profile of risperidone. 750 73

Phase II clinical trials with risperidone have proven it to have a potent antipsychotic effect, improving both positive and negative symptoms of schizophrenia. It was found to have a low potential for inducing extrapyramidal symptoms and has been shown to have a possible antidyskinetic effect without increasing parkinsonism. Risperidone has a rapid onset of action and a favourable side-effect profile. One-year data on risperidone suggest that its therapeutic action in patients with chronic schizophrenia can be maintained without the significant neurological side-effects associated with the use of standard neuroleptics.
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PMID:Clinical review of risperidone. 750 74

Risperidone (Risperdal) is a novel antipsychotic drug, with beneficial effects on both positive and negative symptoms of schizophrenia, and with a low incidence of extrapyramidal side effects (EPS). These particular properties have been attributed to the predominant and very potent serotonin 5-HT2 receptor antagonism of the drug combined with less potent dopamine D2 antagonism. In order to provide data on the degree to which various central neurotransmitter receptors are occupied in vivo, we performed ex vivo receptor occupancy studies with risperidone in comparison with clozapine and haloperidol in rats and guinea pigs. Various types of receptors, to which the compounds were known to bind to in vitro, were investigated precisely using receptor autoradiography in sections of the same rat brain except for histamine H1 receptors that were measured in the guinea-pig cerebellum. Risperidone (2 h after s.c. treatment) occupied 5-HT2 receptors at very low doses (ED50 = 0.067 mg/kg). Nearly full occupancy (> 80%) was achieved before H1, D2, alpha 1 and alpha 2 receptors became occupied (ED50 = 0.45, 0.66, 0.75 and 3.7 mg/kg, respectively). Clozapine displayed occupancy of H1 and alpha 1 receptors at low doses (ED50 = 0.15 and 0.58 mg/kg, respectively) and of 5-HT2, 5-HT1C, D2, alpha 2, cholinergic muscarinic and 5-HT1A receptors at higher doses (ED50 = 1.3, 1.8, 9.0, 9.5, 11 and 15 mg/kg, respectively). Haloperidol occupied D2 and alpha 1 receptors at low doses (ED50 = 0.13 and 0.42 mg/kg, respectively) and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Occupancy of receptor types occurred with similar ED50-values in various brain areas, e.g. D2 receptors in striatum and mesolimbic areas. The ED50-values for the ex vivo measured occupancy of 5-HT2 and D2 receptors were in good agreement with ED50-values for functional effects putatively mediated by these central receptors. The dose-dependent occupancy of D2 receptors proceeded more gradually with risperidone (slope in the caudate-putamen: 0.85) than with clozapine (slope: 1.44) or haloperidol (slope: 1.51). It has previously been suggested that partial D2 receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D2 receptor occupancy would induce extrapyramidal symptoms (EPS). The dose ratio for high (75%) vs. low (25%) D2 receptor occupancy in the caudate-putamen, was 37.3 for risperidone, 8.4 for clozapine, and 7.9 for haloperidol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography. 751 May 74

Dopaminergic hyperactivity mediated via D2 receptors is implicated in the etiology of positive symptoms of schizophrenia, but selective D2 antagonists provide imperfect therapy. This article describes a subanalysis of a trial of risperidone, a combined 5-HT2A/D2 antagonist, in 513 patients with DSM-III-R chronic schizophrenia. Risperidone at 2, 6, 10, and 16 mg/day was compared with placebo and haloperidol 20 mg/day. All doses of risperidone and the 20-mg dose of haloperidol were superior to placebo (mean change from baseline on the PANSS positive and general psychopathology subscales). The 6-mg dose of risperidone also produced significantly more improvement than haloperidol 20 mg. We conclude that risperidone is an effective drug for patients with positive features of schizophrenia.
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PMID:Efficacy of risperidone on positive features of schizophrenia. 752 Sep 4

This article reviews the definitions of negative symptoms and the deficit syndrome of schizophrenia, rating scale criteria (the Scale for Assessment of Negative Symptoms and the Positive and Negative Syndrome Scale), Crow's Type II syndrome, and Carpenter's deficit syndrome in relation to the DSM-IV. The effectiveness of conventional neuroleptics against negative symptoms is still in question. Improvement in negative symptoms may occur in tandem with improvement in the florid symptoms of schizophrenia, but negative symptoms may be difficult to discriminate from the extrapyramidal side effects that are caused by conventional neuroleptics. In a multicenter trial comparing the novel antipsychotic risperidone with haloperidol and placebo in symptomatic schizophrenia, negative symptoms (assessed using the Positive and Negative Syndrome Scale) were reduced more by risperidone at a dose of 6, 10, and 16 mg/day than by placebo. Haloperidol at a dose of 20 mg/day was not significantly better than placebo. Risperidone 6 mg was the lowest dose that produced substantial change in negative symptoms and no increase in extrapyramidal symptoms and antiparkinsonian medication use.
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PMID:Negative symptoms in schizophrenia: assessment of the effect of risperidone. 752 Sep 5


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