Enhanced oral delivery of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations: in-vitro and ex-vivo assessment.

CONTEXT: The oral delivery of risperidone encounters a number of problems, such as pH dependent solubility and low bioavailability, due to its lipophilicity and aqueous insolubility. OBJECTIVE: To improve the solubility, dissolution and intestinal permeation thereby bioavailability of risperidone through a novel self-nanoemulsifying powder (SNEP) formulations. MATERIALS AND METHODS: Oleic acid, Tween® 20, PEG 600 and Aerosil® 200 were chosen as oil, surfactant, co-surfactant and carrier, respectively from solubility and emulsification studies. Ternary phase diagram was constructed to determine emulsifying region. RESULTS AND DISCUSSION: The Z-average and polydispersity Index of developed formulation was 83.1 nm and 0.306, respectively. Ex vivo permeation studies on isolated rat intestine indicated that the amount of risperidone permeated from SNEP formulation was increased around 4- and 1.8-fold than that of pure drug and marketed formulation, respectively. CONCLUSION: This developed SNEP formulations can be regarded as novel and commercially feasible alternative to the current risperidone formulations.

Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure.

Risperidone is a second-generation antipsychotic that causes weight gain. We hypothesized that risperidone-induced shifts in the gut microbiome are mechanistically involved in its metabolic consequences. Wild-type female C57BL/6J mice treated with risperidone (80 µg/day) exhibited significant excess weight gain, due to reduced energy expenditure, which correlated with an altered gut microbiome. Fecal transplant from risperidone-treated mice caused a 16% reduction in total resting metabolic rate in naïve recipients, attributable to suppression of non-aerobic metabolism. Risperidone inhibited growth of cultured fecal bacteria grown anaerobically more than those grown aerobically. Finally, transplant of the fecal phage fraction from risperidone-treated mice was sufficient to cause excess weight gain in naïve recipients, again through reduced energy expenditure. Collectively, these data highlight a major role for the gut microbiome in weight gain following chronic use of risperidone, and specifically implicates the modulation of non-aerobic resting metabolism in this mechanism.

Dopamine D2 receptor occupancy as a predictor of catalepsy in rats: a pharmacokinetic-pharmacodynamic modeling approach.

OBJECTIVES: Dopamine D2 receptor occupancy (D2RO) is the major determinant of efficacy and safety in schizophrenia drug therapy. Excessive D2RO (>80%) is known to cause catalepsy (CAT) in rats and extrapyramidal side effects (EPS) in human. The objective of this study was to use pharmacokinetic and pharmacodynamic modeling tools to relate CAT with D2RO in rats and to compare that with the relationship between D2RO and EPS in humans. METHODS: Severity of CAT was assessed in rats at hourly intervals over a period of 8 h after antipsychotic drug treatment. An indirect response model with and without Markov elements was used to explain the relationship of D2RO and CAT. RESULTS: Both models explained the CAT data well for olanzapine, paliperidone and risperidone. However, only the model with the Markov elements predicted the CAT severity well for clozapine and haloperidol. The relationship between CAT scores in rat and EPS scores in humans was implemented in a quantitative manner. Risk of EPS not exceeding 10% over placebo correlates with less than 86% D2RO and less than 30% probability of CAT events in rats. CONCLUSION: A quantitative relationship between rat CAT and human EPS was elucidated and may be used in drug discovery to predict the risk of EPS in humans from D2RO and CAT scores measured in rats.

Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625.

RATIONALE: α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored. OBJECTIVES: We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914. METHODS: Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914. RESULTS: WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction. CONCLUSIONS: These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.

Neuroleptics in the treatment of aggressive challenging behaviour for people with intellectual disabilities: a randomised controlled trial (NACHBID).

OBJECTIVE(S): To assess the effects and cost-effectiveness of haloperidol, risperidone and placebo on aggressive challenging behaviour in adults with intellectual disability. DESIGN: A double-blind randomised controlled trial of two drugs and placebo administered in flexible dosage, with full, independent assessments of aggressive and aberrant behaviour, global improvement, carer burden, quality of life and adverse drug effects at baseline, 4, 12 and 26 weeks, and comparison of total care costs in the 6 months before and after randomisation. At 12 weeks, patients were given the option of leaving the trial or continuing until 26 weeks. Assessments of observed aggression were also carried out with key workers at weekly intervals throughout the trial. SETTING: Patients were recruited from all those being treated by intellectual disability services in eight sites in England, one in Wales and one in Queensland, Australia. PARTICIPANTS: Patients from all severity levels of intellectual disability; recruitment was extended to include those who may have been treated with neuroleptic drugs in the past. EXCLUSION CRITERIA: treatment with depot neuroleptics/another form of injected neuroleptic medication within the last 3 months; continuous oral neuroleptic medication within the last week; those under a section of the Mental Health Act 1983 or Queensland Mental Health Act 2000. INTERVENTIONS: Randomisation to treatment with haloperidol (a typical neuroleptic drug), risperidone (an atypical neuroleptic drug) or placebo using a permuted blocks procedure. Dosages were: haloperidol 1.25-5.0 mg daily; risperidone 0.5-2.0 mg daily. MAIN OUTCOME MEASURES: Primary: reduction in aggressive episodes between baseline and 4 weeks using Modified Overt Aggression Scale. Secondary: Aberrant Behaviour Checklist; Uplift/Burden Scale; 40-item Quality of Life Questionnaire; Udvalg for Kliniske Undersøgelser scale; Clinical Global Impressions scale. Economic costs recorded using a modified version of Client Service Receipt Inventory for 6 months before and after randomisation. RESULTS: There were considerable difficulties in recruitment because of ethical and consent doubts. Twenty-two clinicians recruited a total of 86 patients. Mean daily dosages were 1.07 mg rising to 1.78 mg for risperidone and 2.54 mg rising to 2.94 mg for haloperidol. Aggression declined dramatically with all three treatments by 4 weeks, with placebo showing the greatest reduction (79%, versus 57% for combined drugs) (p = 0.06). Placebo-treated patients showed no evidence of inferior response in comparison to patients receiving neuroleptic drugs. An additional study found that clinicians who had not participated in clinical trials before were less likely to recruit. Mean total cost of accommodation, services, informal care and treatment over the 6 months of the trial was 16,336 pounds for placebo, 17,626 pounds for haloperidol and 18,954 pounds for risperidone. CONCLUSIONS: There were no significant important benefits conferred by treatment with risperidone or haloperidol, and treatment with these drugs was not cost-effective. While neuroleptic drugs may be of value in the treatment of aggressive behaviour in some patients with intellectual disability, the underlying pathology needs to be evaluated before these are given. The specific diagnostic indications for such treatment require further investigation. Prescription of low doses of neuroleptic drugs in intellectual disability on the grounds of greater responsiveness and greater liability to adverse effects also needs to be re-examined.

Cost-effectiveness and budget impact of long-acting risperidone in Portugal: a modeling exercise.

BACKGROUND: Previous analyses have shown that long-acting risperidone (LAR) is cost-effective in several Western countries. In Portugal, however, the costs of key services are lower. Therefore, available evidence in other countries may have limited relevance. OBJECTIVE: To estimate costs and effects of LAR versus a conventional depot and a short-acting oral atypical antipsychotic over a 5-year period in Portugal. METHODS: An existing discrete event model was adapted to reflect the Portuguese healthcare setting, based on expert opinion, clinical, epidemiological, and cost data. The model compares three scenarios. In scenario 1, patients start with a conventional depot; in scenario 2, with LAR; and in scenario 3, with oral risperidone. The model simulates individual patient histories while taking into account patient characteristics such as risk to society and side-effects. Subsequently, the model simulates patient histories in terms of outpatient appointments, psychotic episodes, treatment, compliance, symptom scores, lack of ability to take care presenting an actual risk, and treatment setting. Outcomes were number of psychotic episodes, cumulative symptom score and direct medical costs. Univariate sensitivity analyses were carried out. RESULTS: Compared to a conventional depot and an oral atypical, LAR was estimated to save approximately euro 3603 and euro 4682 per patient (respectively) and avoid 0.44 and 0.59 relapses per patient in 5 years. Sensitivity analyses showed that the outcome of dominance was only sensitive to estimates about unit costs of hospital/institutionalization, potential risk, and to the reduction in symptoms by use of atypicals. CONCLUSION: Based on this modeling exercise, it could be expected that LAR may be a cost-effective treatment with limited budget impact in Portugal. However, further studies are required to test the generalizability of the results of the present modeling study to the larger population of Portugal.

Risperidone: a review of its use in the treatment of bipolar mania.

Risperidone (Risperdal) is an atypical antipsychotic with high affinity for 5-hydroxytryptamine (5-HT)2A, dopamine D2 and alpha1- and alpha2-adrenergic receptors. Risperidone is now approved in the UK and the US for use in bipolar mania. Risperidone < or =6 mg/day, as monotherapy or adjunctive therapy with first-line mood stabilisers, significantly improves moderate and severe bipolar mania and improves global functioning over 3 weeks. Improvements in Young Mania Rating Scale (YMRS) scores in double-blind trials were greater with risperidone than with placebo over 3 weeks, and similar to those with haloperidol over 3 and 12 weeks. Risperidone was reasonably well tolerated. Limited data are available on the combination of risperidone and carbamazepine. Risperidone, as monotherapy or combined therapy with lithium or valproate semisodium, is an effective treatment option in bipolar mania.

Risperidone in acute and long-term therapy of schizophrenia--a clinical profile.

Data from a range of well-controlled clinical trials, observational studies, and clinical use support the efficacy of risperidone for both acute and long-term therapy of schizophrenic psychoses. With regard to positive symptoms, the efficacy of risperidone was shown to be at least comparable with that of haloperidol. However, risperidone differs from conventional antipsychotics because it is more effective against the negative symptoms, has beneficial effects on affective and cognitive symptoms, and carries less risk of extrapyramidal side effects (EPS). To date, risperidone is the only atypical antipsychotic to have shown a significantly lower relapse rate compared with haloperidol in a long-term double-blind trial. This review describes comprehensive trial data and therapeutic observations gained with risperidone in the treatment of schizophrenia since its approval.

Outcomes and costs of treatment with risperidone in adult and elderly patients: the Delta patient using risperidone study.

PURPOSE: The primary aim of the present study (called DePUR: Delta patients using risperidone) was to compare patient characteristics, treatment outcome variables and medication costs of adult and elderly patients treated with risperidone. METHODS: In a single-centre retrospective study, the following data were extracted from the medical records of 32 adult (< 65 years) and 32 elderly (> or = 65 years) inpatients to whom risperidone was prescribed shortly after admission: demographic data, diagnosis, medication and hospitalisation history, all drugs taken during admission, treatment effectiveness of risperidone, reported adverse events. These data were collected for the period from admission until discharge or until they had been hospitalised for 120 days. RESULTS: Most patients (81% of adult patients and 91% of elderly patients) received risperidone for a psychiatric disease other than schizophrenia. In elderly patients, major depressive disorder with psychotic features was the most frequent diagnosis. Treatment with risperidone was in most cases effective (72% and 74%, respectively), but effectiveness was established sooner in the adult patients than in the elderly patients (7 versus 14 days). The length of stay in hospital was shorter in adults than in elderly (38.5 versus 92.7 days). The daily dose of risperidone was higher in adults than in elderly patients (3.6 versus 1.7 mg per day). Contrary to expectations, daily drug cost of risperidone and daily drug cost of all inpatient drugs were not cheaper in adult patients than in the elderly, mainly due to a higher dose of risperidone and a higher consumption of antipsychotic co-medication in adults. CONCLUSION: Risperidone is prescribed successfully for many other psychotic features than for schizophrenia. Treatment of elderly patients in our clinic does not require higher daily medication costs than for adult patients.

Hyperglycemic clamp assessment of insulin secretory responses in normal subjects treated with olanzapine, risperidone, or placebo.

The goal of this study was to evaluate the effect of olanzapine or risperidone treatment on beta-cell function in healthy volunteers. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d; n = 17), risperidone (4 mg/d; n = 13), or placebo (n = 18) for 15-17 d. Insulin secretion was quantitatively assessed at baseline and the end of the study period using the hyperglycemic clamp. Weight increased significantly (P < 0.01) in the olanzapine (2.8 +/- 1.7 kg) and risperidone (3.1 +/- 2.1 kg) treatment groups. An increase ( approximately 25%) in the insulin response to hyperglycemia and a decrease ( approximately 18%) in the insulin sensitivity index were observed after treatment with olanzapine and risperidone. The change in insulin response was correlated (r = 0.5576; P = 0.019) with a change in body mass index. When the impact of weight change was accounted for by multivariate regression analyses, no significant change in insulin response or insulin sensitivity was detected after treatment with olanzapine or risperidone. We found no evidence that treatment of healthy volunteers with olanzapine or risperidone decreased the insulin secretory response to a prolonged hyperglycemic challenge. The results of this study do not support the hypothesis that olanzapine or risperidone directly impair pancreatic beta-cell function.

Tolerability and effectiveness of atypical antipsychotics in male geriatric inpatients.

The atypical antipsychotics are gradually becoming the mainstay of treatment for psychosis in the elderly. The present study examines the effectiveness and tolerability of risperidone and olanzapine treatment in 34 matched male patients admitted to a VA Medical Center geriatric inpatient unit. The Positive and Negative Syndrome Scale for Schizophrenia (PANSS), the Cohen-Mansfield Agitation Inventory (CMAI), the Rating Scale for Side-Effects, the Extra-Pyramidal Rating Scale, and the Mini-Mental State Examination were administered at admission and discharge. T-tests at admission and discharge across groups indicate that the patients as a whole were performing significantly better following their stay on the CMAI (t(30)=4.31, p=0.000), the GAF (t(31)=9.73, p=0.000), the PANSS total score (t(29)=3.82, p=0.001), and the positive symptom portion of the PANSS (t(28)=4.29, p=0.000). No significant differences were detected between the two groups with regard to length of hospitalization, or reduction in scores on the PANSS, or CMAI, however the daily cost of risperidone was 1/3 as much as olanzapine (p=0.00). The two treatments were comparable in the elderly men evaluated in this study.

New antipsychotic medications: what advantages do they offer?

New, so-called atypical antipsychotic medications will no doubt supplant the traditional, or "typical," antipsychotic medications, just as the new generation of antidepressant agents has replaced the older tricyclic drugs. At issue with most of the new drugs is not acute efficacy, but long-term tolerability. Side effects must be minimized to enhance compliance and prevent relapse. It appears that many of the new antipsychotic drugs have fewer or less troublesome side effects than the older agents. In addition, the "atypical" antipsychotic agents hold promise for treating refractory schizophrenia. At present, only clozapine, with its risks for agranulocytosis and seizures, is clearly established as a treatment for refractory illness. Risperidone may be an alternative for treatment-resistant schizophrenia, but this has not yet been clearly proved. Olanzapine has recently been introduced. Sertindole should be available soon, and quetiapine and ziprasidone should quickly follow. Safety, efficacy, and cost will guide their use. None of these newer agents have been compared head-to-head with clozapine. More research is needed to place these new drugs into clinical perspective.