SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
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)
Risperidone, a new antipsychotic agent which antagonizes both 5-hydroxytryptamine-2 (5-HT2) and dopamine-2 (D2) receptors, was evaluated for its effects on prolactin release. One hr after either p.o. or i.p. dosing, risperidone was 3 to 5 times more potent than the classical D2 receptor antagonist haloperidol in stimulating rat prolactin levels in vivo. This result was unexpected because haloperidol is a more potent D2 receptor antagonist than risperidone in vitro. Mechanisms which might explain these observations were investigated. Compared to haloperidol, risperidone was 0.34 (95% confidence interval: 0.23, 0.48) times as potent in reversing the suppression by dopamine of rat anterior pituitary cell prolactin release in vitro, which is consistent with the compounds' striatal D2 receptor binding potencies in vitro. Administration of ketanserin, a 5-HT2 receptor antagonist, along with haloperidol did not modify haloperidol's activity on either in vitro pituitary cell prolactin release (up to 1000 nM ketanserin) or in vivo prolactin concentrations (5 mg/kg ketanserin, i.p.). In vitro incubation of haloperidol and risperidone with a liver homogenate supernatant (S-9) led to extensive (greater than 86%) metabolism of each compound. S-9 treatment abolished haloperidol's effects on pituitary cell prolactin release. Risperidone's ability to increase prolactin release was unchanged after S-9 treatment, and 9-hydroxy-risperidone, identified as a major metabolite in the S-9 conditioned media, was equipotent to risperidone in modulating prolactin release in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Forty-four chronic schizophrenic inpatients participated in this multicentre 12-week parallel-group double-blind trial. After a run-in period of 2 weeks and a single-blind placebo wash-out of 1 week, they were randomly assigned to treatment with either the serotonin2 and dopamine-D2 antagonist risperidone or haloperidol. Two patients were excluded from the efficacy analysis. Five patients dropped out in the haloperidol group and 1 in the risperidone group. At the end of the trial, the mean daily dose was 12 mg for risperidone and 10 mg for haloperidol. The risperidone group showed greater improvement on the Positive and Negative Syndrome Scale for Schizophrenia, the Schedule for Affective Disorders and Schizophrenia-change version, and the Nurses' Observation Scale for Inpatient Evaluation. The improvement of negative symptoms was more pronounced in the risperidone group until week 8 of double-blind treatment. The consumption of antiparkinsonian medication was 10 times lower with risperidone. Both drugs were well tolerated and the laboratory, endocrinological and cardiovascular safety parameters were comparable. This study suggests that risperidone is comparable to haloperidol as an antipsychotic, but that it has a safer EPS profile.
Risperidone represents a unique pharmacology of potent antagonism of both serotonin and dopamine receptors. In a randomized, parallel-group, double-blind trial of risperidone vs. haloperidol and placebo in 36 schizophrenic patients in acute exacerbation, risperidone showed a quicker onset of antipsychotic activity than did haloperidol. Risperidone treatment was statistically superior to placebo, with a trend toward superiority to haloperidol. Risperidone did not differ from placebo on assessment scales of extrapyramidal side effects, but produced significantly less than did haloperidol. There were no major adverse reactions associated with risperidone use, but it was noted to reduce the signs of tardive dyskinesia. This study suggests that risperidone may offer a superior side-effect profile, and possibly greater efficacy, than a standard neuroleptic such as haloperidol.
OBJECTIVE: The CYP2D6*10 allele, which is prevalent in the Indian population, is of particular clinical significance. This study aims to investigate the effect of the CYP2D6*10 allele on the pharmacokinetics of risperidone and its metabolites following single-dose administration in healthy South Indian volunteers. METHODS: The study was conducted with twenty healthy volunteers who were administered a single 2 mg dose of risperidone. CYP2D6 genotyping was performed using the PCR-RFLP method. Plasma levels of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OHRIS) were quantified using a UPLC-DAD system. RESULTS: Significant differences in pharmacokinetic parameters were observed across the CYP2D6*10 genotypes. For intermediate metabolizers, the Cmax, AUC0-t, and T1/2 were approximately 1.2 times higher, and the metabolic ratio was double compared to normal metabolizers. Notably, the Cmax of the active moiety was significantly higher in intermediate metabolizers compared to normal metabolizers (p < 0.05). These findings indicate that CYP2D6 polymorphisms are associated with altered pharmacokinetic profiles of risperidone, with a reduced metabolic activation in individuals carrying the *10 allele. CONCLUSION: The results suggest that CYP2D6 genotyping could help inform personalized dosing strategies for risperidone, though further randomized controlled trials are required to confirm these findings.
BACKGROUND: There are few and conflicting data on the role of cytochrome P450 2D6 (CYP2D6) polymorphisms in relation to risperidone adverse events (AEs) in children. This study assessed the association between CYP2D6 metabolizer status and risk for risperidone AEs in children. METHODS: Children ≤18 years with at least 4 weeks of risperidone exposure were identified using BioVU, a de-identified DNA biobank linked to electronic health record data. The primary outcome of this study was AEs. After DNA sequencing, individuals were classified as CYP2D6 poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. RESULTS: For analysis, the 257 individuals were grouped as poor/intermediate metabolizers (n = 33, 13%) and normal/ultrarapid metabolizers (n = 224, 87%). AEs were more common in poor/intermediate vs. normal/ultrarapid metabolizers (15/33, 46% vs. 61/224, 27%, P = 0.04). In multivariate analysis adjusting for age, sex, race, and initial dose, poor/intermediate metabolizers had increased AE risk (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.1, P = 0.03). CONCLUSION: Children with CYP2D6 poor or intermediate metabolizer phenotypes are at greater risk for risperidone AEs. Pre-prescription genotyping could identify this high-risk subset for an alternate therapy, risperidone dose reduction, and/or increased monitoring for AEs.
The mixed serotonin-2/dopamine-D2 antagonists risperidone and ocaperidone were compared with the specific D2 antagonist haloperidol for their ability to antagonize amphetamine (10 mg/kg, s.c.)-induced stereotypy in rats. Four successive stages of amphetamine antagonism were differentiated: 1) disinhibition: reversal of stationary stereotypy into the hyperactivity normally observed with lower doses of amphetamine; 2) inhibition: the first significant reduction of activity; 3) normalization: reduction of activity to the level of nonamphetaminized rats; and 4) suppression: reduction of activity to 50% of the level of nonamphetaminized rats. Ocaperidone and risperidone were equipotent with haloperidol for disinhibition (0.0062-0.011 mg/kg). However, the disinhibition was maintained over a wider dose range with risperidone (factor 84) than with haloperidol (9.0) and ocaperidone (4.1) and was also more pronounced in magnitude with risperidone. Ocaperidone was equipotent with haloperidol for inhibition (0.013-0.025 mg/kg) and normalization (0.074-0.080 mg/kg) but 4.4 times less potent for suppression of activity (0.71 vs. 0.16 mg/kg). Risperidone became progressively less potent than haloperidol: 4.4 times for inhibition, 9.6 times for normalization and 22 times for suppression of activity. The present data are consistent with the hypothesis that serotonin-2 antagonism compensates for the functional consequences of D2 receptor blockade. The implications for the clinical application of the compounds are discussed.
In vitro receptor-binding profiles and in vivo pharmacological studies have shown risperidone to be a potent mixed serotonin-S2 dopamine-D2-like receptor antagonist. While anti-D2 activity may relate to the antipsychotic potency of neuroleptic drugs, an antidepressive efficacy of substances with anti-S2 activity has been suggested. In an open pilot-study, ten patients with schizodepressive disorders or a DSM-III-R diagnosis of psychotic major depressive episodes were treated with risperidone (2-10 mg/d) for six weeks. Weekly psychopathological evaluation was performed, including BPRS, SANS, SAPS, VAS scales, and AIMS and UKU for the assessment of side-effects. Generally, the psychotic syndrome (BPRS, SANS and SAPS) decreased markedly in all patients; seven patients also showed a clinically significant improvement of depressive symptoms (BPRS). Except for two patients who needed biperiden because of extrapyramidal side-effects, the tolerance of risperidone was good. The antipsychotic and antidepressive properties of risperidone shown in our pilot study are promising enough to merit full double-blind controlled trials for further evaluation of its therapeutic value in this broad spectrum of psychiatric disorders.
This multicenter trial indicates that risperidone is an effective treatment for the positive and negative symptoms of schizophrenia. The most effective dose appears to be about 6 mg of risperidone daily. This dose was more effective than 20 mg of haloperidol. In addition, this dose was associated with very low rates of extrapyramidal side effects.
A high-performance liquid chromatographic method has been developed for the simultaneous determination of the new antipsychotic risperidone and its major metabolite 9-hydroxyrisperidone in plasma, urine and animal tissues. The alkalinized plasma samples were extracted with ethyl acetate and further purified prior to reversed-phase chromatography with ultraviolet detection at 280 nm. The method could also be applied to urine samples and animal tissue homogenates. Quantification limits were 2 ng/ml for plasma and urine and 10 ng/g for animal tissue. The method was applied to pharmacokinetic studies in experimental animals, human volunteers and patients.
TV-46000 is a long-acting injectable antipsychotic (LAI) approved for the treatment of adults with schizophrenia and bipolar I disorder. LAIs like TV-46000 can improve adherence and reduce relapse in patients with schizophrenia; however, injection site reactions (ISRs) can contribute to LAI discontinuation. ISRs with TV-46000 treatment were characterized using data from two phase 3 trials of patients with schizophrenia (RISE [NCT03503318], SHINE [NCT03893825]) and a phase 1 study of patients with schizophrenia or schizoaffective disorder. Patients in the pooled safety population (aged 16-67 years) from RISE and SHINE (n = 525 TV-46000, n = 179 placebo) received 4554 TV-46000 injections and 2721 placebo injections. ISRs were reported in 19 % (n = 102) of patients who received TV-46000, corresponding to an exposure-adjusted event rate (EAER)/100 patient-years of 48.67. ISRs led to 9 (1.7 %) treatment discontinuations of TV-46000. The most frequently reported ISR adverse events were injection site pain (EAER, 15.38, n = 36 [7 %]) and injection site nodule (EAER, 12.01, n = 35 [7 %]). ISR frequency and pain and nodule adverse event frequency decreased after the first injection. In the phase 1 study (n = 99), mean injection site pain scores were highest immediately after injection, showed a notable decrease within 10 min of injection, and further decreased within 1 h after injection. In conclusion, for >4500 injections evaluated, ISR rates with TV-46000 were modest. Most ISRs were mild or moderate and rarely led to treatment discontinuation. Results support the favorable tolerability of TV-46000 as a treatment for schizophrenia in adults.
Explore the source record for details and available documents.
Ocaperidone, a new benzisoxazolyl piperidine neuroleptic, was compared with haloperidol, risperidone and ritanserin in a large series of pharmacological tests. Ocaperidone inhibited dopamine agonist (apomorphine, amphetamine or cocaine)-induced behavioral effects at low doses (0.014-0.042 mg/kg) and was, thereby, equipotent with haloperidol (0.016-0.024 mg/kg) and 2.0 to 8.3 times more potent than risperidone. Ocaperidone completely blocked the dopamine agonist behavior at slightly higher doses (0.064 mg/kg) and was, thereby, more potent and efficacious than haloperidol (0.097-0.13 mg/kg) and risperidone (0.59-1.17 mg/kg). The dissociation between inhibition of apomorphine behavior and induction of catalepsy was as high for ocaperidone (22) as for risperidone (20) and higher than for haloperidol (8), suggesting risperidone-like low extrapyramidal side effect liability. Ocaperidone also antagonized serotonin agonist (tryptamine, mescaline or 5-hydroxytryptophan)-induced behavioral effects (0.011-0.064 mg/kg) and was, thereby, equipotent with risperidone (0.014-0.056 mg/kg) and at least as potent as ritanserin (0.037-0.13 mg/kg). Ocaperidone displayed its serotonin and dopamine antagonism at the same dose levels, in contrast to risperidone, which was a predominant serotonin antagonist. Apart from protection from compound 48/80 lethality (0.042 mg/kg) and norepinephrine lethality (0.097 mg/kg), which were not considered to hinder its clinical application, no additional secondary effects were observed at low doses of ocaperidone. In the apomorphine test in dogs, ocaperidone was very potent (i.v., s.c. and p.o. ED50 values: less than 1.0 micrograms/kg) and showed a rapid onset (less than 0.5 h) and long duration of action (24 h) after p.o. administration. Ocaperidone is concluded to be a highly potent and efficacious dopamine-D2 antagonist with concomitant, equivalent serotonin 5-HT2 antagonism. Ocaperidone is expected to exert pronounced haloperidol-like effects on the positive symptoms of schizophrenic patients but with risperidone-like low extrapyramidal side effect liability and improved patient compliance.
BACKGROUND: The efficacy of intermittent theta-burst stimulation (iTBS) combined with pharmacotherapy and psychotherapy in first-episode schizophrenia remains unclear. This study evaluated adjunctive iTBS with risperidone and cognitive behavioral therapy (CBT) and explored serum biomarkers indicating treatment response. METHODS: In this randomized, assessor-blind trial, 100 first-episode schizophrenia patients received either iTBS plus risperidone and CBT (iTBS group, n = 50) or risperidone and CBT alone (control, n = 50) for 3 months. The primary outcome was change in PANSS total score at 4 weeks and 3 months. Response was defined as a ≥ 50 % PANSS reduction. Secondary outcomes included cognitive function (MCCB subtests) and serum GDNF, cortisol, and dehydroepiandrosterone sulfate (DHEA-S) levels. RESULTS: The iTBS group showed significantly greater reduction in PANSS total scores than controls at both 4 weeks and 3 months (mean difference at 3 months: -13.3, 95 % CI: -16.8 to -9.8; P < 0.001), with a higher responder rate (76 % vs. 48 %). Significant improvements across all cognitive domains were observed in the iTBS group (all P < 0.001). Post-treatment, the iTBS group exhibited higher GDNF and lower cortisol and DHEA-S levels (all P < 0.001). A combined biomarker panel demonstrated superior discriminative performance for treatment efficacy (AUC=0.865 after cross-validation). Adverse events were comparable between groups. CONCLUSIONS: Adding iTBS to risperidone and CBT significantly improves clinical symptoms and cognitive function in first-episode schizophrenia. The combination of GDNF, cortisol, and DHEA-S shows promise as a composite biomarker for treatment response, though sham-controlled validation is warranted.
BACKGROUND: Acute bipolar mania carries negative social and economic consequences. We investigated the comparative efficacy/response/acceptability of pharmacological interventions for acute bipolar mania, considering dose effects across different age groups. METHODS: We conducted a network meta-analysis (NMA) to search for randomized controlled trials (RCTs) comparing pharmacological interventions with one another or placebo in acute bipolar mania patients, indexed in PubMed/MEDLINE, Embase, Web of Science, and Scopus (from inception through 2025.12.24). Co-primary outcomes were change in manic symptoms/response/and acceptability. Tolerability/remission and rate of adverse events were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. RESULTS: 113 RCTs, encompassing 49 distinct treatment combinations, included 20,666 participants. Sensitivity analysis retaining only low-risk-of-bias studies and excluding outliers for possible effect modifiers indicated that risperidone 3 mg/day(SMD = -7.57;95%C.I. = -8.25;-5.85); tamoxifen 160 mg/day(SMD = -1.73;95%C.I. = -2.32;-1.13); rivastigmine 3 mg/day(SMD = -1.13;95%C.I. = -1.06;-0.58); haloperidol 30 mg/day(SMD = -0.96;95%C.I. = -1.25;-0.75); valproate 750 mg/day(SMD = -0.76;95%C.I. = -1.48;-0.58); tamoxifen 40 mg/day(SMD = -0.75;95%C.I. = -1.41;-0.59); celecoxib 400 mg/day(SMD = -0.74;95%C.I. = -1.20;-0.38); paliperidone extended-release 12 mg/day(SMD = -0.62; 95%C.I. = -0.91;-0.32); olanzapine 15 mg/day(SMD = -0.59;95%C.I. = -0.60;-0.38); olanzapine 20 mg/day(SMD = -0.52;95%C.I. = -0.66;-0.38); risperidone 4 mg/day(SMD = -0.53;95%C.I. = -0.76;-0.29); allopurinol 600 mg/day(SMD = -0.54;95%C.I. = -0.67;-0.22); cariprazine 12 mg/day(SMD = -0.49;95%C.I. = -0.66;-0.33); risperidone 4.2 mg/day(SMD = -0.46;95%C.I. = -0.75;-0.17); lithium 1500 mg/day(SMD = -0.42;95%C.I. = -0.57;-0.28); ziprasidone 160 mg/day(SMD = -0.49;95%C.I. = -0.68;-0.31); asenapine 20 mg/day(SMD = -0.38;95%C.I. = -0.53;-0.22); haloperidol 8 mg/day(SMD = -0.34;95%C.I. = -0.63;-0.05); aripiprazole 15 mg/day(SMD = -0.33;95%C.I. = -0.61;-0.06) outperformed placebo. Ziprasidone 160 mg/day, celecoxib 200 mg/day, asenapine 20 mg/day, and asenapine 10 mg/day proved more efficacious than placebo in children. No statistically significant differences were reported between treatments and placebo for response/remission/acceptability/tolerability, and manic/hypomanic switch. A meta-regression of efficacy effect sizes against the adapted AMSTAR-Plus content scores showed that larger SMDs were associated with lower AMSTAR scores, indicating lower study quality, warranting further caution for such large efficacy estimates. CONCLUSIONS: Our findings are consistent with previous NMAs and current guidelines, expanding the current knowledge base while concurrently appraising different drugs, doses, and age groups.
The ventricle-brain ratio (VBR) of 42 chronic schizophrenic patients was compared with that of 42 age-matched medical controls. For the schizophrenics, the relationship of various clinical parameters to the VBR was assessed, and the outcome of 12 weeks of double-blind treatment with either risperidone or haloperidol. The results confirm that schizophrenic patients have slightly enlarged lateral ventricles compared with medical controls. Only for schizophrenics, an effect of age, but not of duration of illness, was noticed. This study does not support the validity of a clinical subdivision of chronic schizophrenic patients on the basis of the VBR. Neither negative, positive nor general psychopathological symptoms, as measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), were related to the VBR, nor were abnormal involuntary movements or extrapyramidal symptoms. No association between season of birth or a family history of major mental disorder and VBR could be demonstrated. Treatment response was predicted by the total PANSS score and the PANSS general psychopathology subscale score at baseline. There was a trend for patients with higher VBR to have a more or haloperidol). or haloperidol).
We determined the affinity and selectivity of binding for 24 compounds: nine antimuscarinics (including some antiparkinson drugs) and 15 neuroleptics (including the atypical compounds clozapine, fluperlapine, melperone, rilapine, risperidone, tenilapine, tiosperone and zotepine) at the five human muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Equilibrium dissociation constants (Kd) were obtained from competitive radioligand binding studies with [3H]quinuclidinyl benzilate and membranal preparations of these cells. As expected, QNB had the highest affinity of the compounds studied at the five receptor subtypes and was not selective (Kd ranged from 0.027-0.088 nM). Benztropine had the next highest affinity of the antimuscarinic compounds and thioridazine had the highest affinity of the neuroleptics. Among the antiparkinson drugs, biperiden was the only one selective for the m1 subtype; and among the neuroleptics, the atypical drug clozapine was also selective for the m1 subtype. This selectivity may explain clozapine's unusual efficacy in refractory schizophrenic patients and its low incidence of extrapyramidal side effects. However, because most other atypical neuroleptics studied lacked high affinity and selectivity at muscarinic receptor subtypes, it is likely that other mechanisms are involved as well.