A risk-benefit assessment of risperidone for the treatment of behavioural and psychological symptoms in dementia.

The importance of behavioural and psychological symptoms in dementia (BPSD) is increasingly being recognised. Symptoms such as verbal and physical aggression, agitation, sleep disturbances and wandering are common, cause great distress to caregivers and are likely to lead to institutionalisation of patients. At present, these symptoms are also more amenable to treatment compared with the progressive intellectual decline caused by dementing illnesses. The care of individuals with BPSD involves a broad range of psychosocial treatments for the patient and his or her family. If pharmacotherapy is deemed necessary to manage BPSD, a careful balance must be struck between the benefits of symptom control and the inherent risks associated with most psychotropic agents in the elderly. Elderly patients in general, and patients with dementia in particular, are more sensitive to medication adverse effects, including anticholinergic effects, orthostatic hypotension, sedation, parkinsonism, tardive dyskinesia and cognitive impairment than younger patients with dementia or individuals without dementia. To date, treatment of symptoms of aggression and psychosis has relied on the empirical use of antidepressants, anxiolytics, typical antipsychotics (neuroleptics) and other agents. Treatment-limiting adverse effects are frequently reported with all of these agents. However, it is the typical antipsychotics and the atypical antipsychotic clozapine that are associated with the greatest risk of adverse effects in the elderly. The present review highlights the issues that limit the use of older psychotropic agents in the elderly, and presents an assessment of the available evidence concerning the efficacy, safety and tolerability of the atypical antipsychotic risperidone, in the treatment of BPSD in elderly patients with dementia. The extensive clinical development programme for risperidone has shown the drug to be effective and well tolerated in many fragile patients. As a result of its efficacy and safety profile, risperidone can be used for the treatment of behavioural and psychological symptoms in patients with dementia. Risperidone therefore represents a significant addition to the armamentarium for BPSD. While efforts continue in the development of treatment for the cognitive decline associated with dementia, treatment is now available for the noncognitive symptoms. By treating the latter, risperidone has the potential to be of substantial benefit to patients with dementia, their carers and the costs of healthcare.     

Quetiapine. A review of its use in the management of schizophrenia

Quetiapine (Seroquel), a dibenzothiazepine derivative, is an atypical antipsychotic with demonstrated efficacy in acute schizophrenia. In short-term, randomised, double-blind trials, it was usually more effective than placebo, and was generally effective against both positive and negative symptoms. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (up to 750 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in patients with acute schizophrenia in randomised, double-blind trials; it was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous antipsychotic treatment. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (up to 800 mg/day) were similar to those with risperidone (up to 8 mg/day) or olanzapine (15 mg/day) [interim analysis]. Efficacy was maintained for at least 52 weeks in open-label follow-up studies in adult and elderly patients. Quetiapine improved cognitive function versus haloperidol, and depressive symptoms and hostility/aggression versus placebo. Quetiapine is well tolerated. It is associated with placebo-level incidence of extrapyramidal symptoms (EPS) across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g. the elderly, adolescents or patients with organic brain disorders) and has a more favourable EPS profile than risperidone. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even normalise. Quetiapine appears to have minimal short-term effects on bodyweight and a favourable long-term bodyweight profile. Preliminary studies indicate that there is a high level of patient acceptability and satisfaction with quetiapine. In conclusion, quetiapine has shown efficacy against both positive and negative symptoms of schizophrenia, and has benefits in improving cognitive deficits, affective symptoms and aggression/hostility. The beneficial effects of quetiapine have been maintained for at least 52 weeks. Quetiapine was effective and well tolerated in hard-to-treat patients, and may be of particular use in these individuals. It is at least as effective as standard antipsychotics and appears to have similar efficacy to risperidone and olanzapine. The relative risk/benefit profile of quetiapine compared with other atypical antipsychotics requires further research in head-to-head trials, although quetiapine's relatively benign tolerability profile distinguishes it from other commonly used atypical agents, particularly with respect to bodyweight, EPS and plasma prolactin levels. Overall, quetiapine has an excellent risk/benefit profile and is a suitable first-line option for the treatment of schizophrenia.     

Risperidone versus haloperidol in the treatment of acute exacerbations of chronic inpatients with schizophrenia: a randomized double-blind study.

The purpose of this study was to compare the efficacy and safety of risperidone and haloperidol in treatment-resistant chronic schizophrenic patients. Subjects (n = 78) who met DSM-III criteria for schizophrenia were randomly assigned to receive 6 mg/day of risperidone or 20 mg/day of haloperidol for 12 weeks. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS), and side-effects with the Treatment Emergent Symptom Scale (TESS). Risperidone produced a mean 39.8 +/- 24.1% reduction in total PANSS score compared to a mean 28.3 + 19.4% reduction in the haloperidol group (P < 0.05). Analysis of changes for the three subscores of the PANSS revealed that the general psychopathology and negative subscores were significantly improved in the risperidone group compared to the haloperidol group. As for the side-effects, the risperidone group showed a significantly lower TESS total score, as well as nervous system symptoms subscore and cardiovascular symptoms subscore, compared to the haloperidol group. Risperidone appears to be a more effective and better tolerated antipsychotic drug in treatment-refractory Chinese schizophrenia than haloperidol.     

Risperidone in the management of psychiatric and neurodegenerative disease in the elderly: an update

OBJECTIVE: Neuropsychiatric disorders are common among elderly patients in long-term care facilities. Although dementia is most common, schizophrenia and schizoaffective disorder, delusional disorder, bipolar disorder, and Parkinson's disease, as well as other psychiatric and neurodegenerative disorders, can also occur in this population. Our objective was to review the literature pertaining to the safety and efficacy of risperidone in elderly patients, the atypical antipsychotic with the longest history of use in this population. We identified original studies of risperidone in elderly patients through MEDLINE and CURRENT CONTENTS database searches. Additional material was identified via abstracts presented at national and international conferences. Published data from controlled and uncontrolled trials in elderly patients support the efficacy of risperidone in controlling behavioral and psychological symptoms of dementia, as well as treating psychotic symptoms associated with schizophrenia and other disorders with psychotic features. Limited data suggest that risperidone might also be useful for management of patients with delirium and Huntington's disease. Risperidone was well tolerated in the elderly and associated with a low risk of movement disorders and anticholinergic effects. A recent change in the product information described an increased incidence of cerebrovascular events in some elderly and suggests the need for further investigations in this population. There is a substantial published database supporting safe and effective use of risperidone for treatment of psychosis, agitation, and aggression in elderly patients.     

Short-term treatment with risperidone or haloperidol in first-episode schizophrenia: 8-week results of a randomized controlled trial within the German Research Network on Schizophrenia

Patients with first-episode schizophrenia appear to respond to lower doses of neuroleptics, and to be more sensitive to developing extrapyramidal side-effects. The authors therefore compared in such patients the efficacy and extrapyramidal tolerability of comparatively low dosages of the atypical neuroleptic risperidone and of the conventional neuroleptic haloperidol. Risperidone was hypothesized to have better extrapyramidal tolerability and efficacy in treating negative symptoms. Patients were randomly assigned under double-blind conditions to receive risperidone (n=143) or haloperidol (n=146) for 8 wk. The primary efficacy criterion was the estimated difference in the mean change in the Positive and Negative Symptom Scale (PANSS) negative score between treatment groups; secondary efficacy criteria were changes on the PANSS total score and other PANSS subscores, and several other measures of psychopathology and general functioning. The primary tolerability criterion was the difference in baseline-adjusted occurrence rates of extrapyramidal side-effects measured with the Simpson-Angus Scale (SAS) compared between treatment groups. The main hypothesis was that risperidone would be superior in terms of improving negative symptoms and lowering the risk of extrapyramidal symptoms. Secondary tolerability criteria were the other extrapyramidal symptoms, measured with the Hillside Akathisia Scale (HAS) and the Abnormal Involuntary Movement Scale (AIMS). The average mean daily doses were 3.8 mg (s.d.=1.5) for risperidone and 3.7 mg (s.d.=1.5) for haloperidol. There were similar, significant improvements in both treatment groups in the primary and secondary efficacy criteria. At week 8 nearly all scores of extrapyramidal side-effects indicated a significantly higher prevalence of extrapyramidal side-effects with haloperidol than with risperidone [SAS: risperidone 36.5% of patients; haloperidol 51.5% of patients; likelihood ratio test, chi2(1)=7.8, p=0.005]. There were significantly fewer drop-outs [risperidone n=55, drop-out rate=38.5%; haloperidol n=79, drop-out rate=54.1%, chi2(1)=7.1, p=0.009] and a longer non-discontinuation time [risperidone: average of 50.8 d to drop-out; haloperidol: average of 44.0 d to drop-out; log rank test, chi2(1)=6.4, p=0.011] in the risperidone group. Risperidone and haloperidol appear to be equally effective in treating negative and other symptoms of first-episode schizophrenia. Risperidone has better extrapyramidal tolerability and treatment retention rate than the equivalent dose of haloperidol in these patients.     

Shifting from haloperidol to risperidone for behavioral disturbances in dementia: safety, response predictors, and mood effects.

For agitated dementia showing insufficient response to conventional antipsychotics, the feasibility of transition to atypical agents remains unknown. Sixty-two Chinese inpatients with dementia and disruptive behaviors were recruited into an 8-week screening trial of haloperidol. Thirty-five (56%) of them responded insufficiently. They then entered a prospective, 16-week, open-labeled study. Haloperidol was abruptly shifted to risperidone 0.5 mg/day at weeks 1 to 4 and then 1 mg/day at weeks 5 to 12. At weeks 13 to 16, the regimen was shifted back to haloperidol at previous doses, mostly 1 mg/day. Safety, efficacy, cognition, and moods were evaluated at least every 4 weeks. Generalized estimating equation methods were used for determining the effects of the prognostic variables on the outcome values. Risperidone, particularly at 0.5 mg/day, was generally tolerable. The Brief Psychiatric Rating Scale (BPRS) score decreased progressively under risperidone treatment; at week 12, 16 (46%) patients showed response (>or=25% reduction in the BPRS). Patients with vascular dementia were more likely to respond than those with Alzheimer's disease ( p = 0.02). Haloperidol reinstitution resulted in no further improvement, except trend increments in motor symptoms. Risperidone also tended to benefit the performance on the Behavioral Pathology in Alzheimer's Disease Rating Scale. Six (17%) patients improved on moods and self-care with risperidone. These preliminary results suggest that crossover from haloperidol to risperidone is generally safe and effective and may produce favorable moods in agitated dementia patients. Vascular dementia is a predictor of treatment response. In contrast to the dose (1 mg/day) recommended for most white individuals, 0.5 mg/day could be tried at first in Chinese patients. Because of the design's limitations, further controlled studies are warranted.     

Amisulpride: a review of its use in the management of schizophrenia.

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors. At higher doses, amisupride antagonises postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or =300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. CONCLUSION: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

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.     

Spotlight on amisulpride in schizophrenia

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D(2)/D(3) autoreceptors. At higher doses, amisulpride antagonises postsynaptic D(2) and D(3) receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or = 1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or = 300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. Conclusion: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or = 1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

A double-blind, controlled study of sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia

Sertindole is a non-sedating atypical antipsychotic effective in the management of schizophrenia and is associated with placebo-level incidence of extrapyramidal symptoms (EPS). In this randomized, double-blind, parallel-group, flexible-dose, multi-centre study, the efficacy and tolerability of sertindole was directly compared with another atypical antipsychotic in patients with schizophrenia. A total of 187 patients were randomly assigned to treatment with sertindole (12-24 mg/day, n=98) or risperidone (4-10 mg/day, n=89) for 12 weeks. Although early termination reduced the power of the study, some significant between-group differences were evident. Sertindole reduced the mean Positive and Negative Syndrome Scale total scores to a greater extent than risperidone, and the difference reached statistical significance at endpoint for the Observed Cases (OC) dataset. Moreover, sertindole was superior for the treatment of negative symptoms compared to risperidone (P<0.05, Last Observation Carried Forward and OC). Both treatment groups were similarly effective in improving Clinical Global Impression (Severity and Improvement), the Drug Attitude Inventory and Global Assessment of Functioning scores. Sertindole and risperidone were both well tolerated. Numerically, fewer patients in the sertindole group (19%) reported EPS-related adverse events than in the risperidone group (28%), although significantly more sertindole-treated patients reported QT prolongation and abnormal ejaculation volume (P<0.05). In conclusion, sertindole was well tolerated and demonstrated clinically relevant efficacy advantages over risperidone.     

Olanzapine: an updated review of its use in the management of schizophrenia

Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has proven efficacy against the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall improvements in psychopathology rating scales and in the treatment of depressive and negative symptoms, and was comparable in effects on positive psychotic symptoms. The 1-year risk of relapse (rehospitalisation) was significantly lower with olanzapine than with haloperidol treatment. In the first double-blind comparative study (28-week) of olanzapine and risperidone, olanzapine 10 to 20 mg/day proved to be significantly more effective than risperidone 4 to 12 mg/day in the treatment of negative and depressive symptoms but not on overall psychopathology symptoms. In contrast, preliminary results from an 8-week controlled study suggested risperidone 2 to 6 mg/day was superior to olanzapine 5 to 20 mg/day against positive and anxiety/depressive symptoms (p < 0.05), although consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology. Improvements in general cognitive function seen with olanzapine treatment in a 1-year controlled study of patients with early-phase schizophrenia, were significantly greater than changes seen with either risperidone or haloperidol. However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects of olanzapine and risperidone treatment in patients with schizophrenia or schizoaffective disorder. Several studies indicate that olanzapine has benefits against symptoms of aggression and agitation, while other studies strongly support the effectiveness of olanzapine in the treatment of depressive symptomatology. Olanzapine is associated with significantly fewer extrapyramidal symptoms than haloperidol and risperidone. In addition, olanzapine is not associated with a risk of agranulocytosis as seen with clozapine or clinically significant hyperprolactinaemia as seen with risperidone or prolongation of the QT interval. The most common adverse effects reported with olanzapine are bodyweight gain, somnolence, dizziness, anticholinergic effects (constipation and dry mouth) and transient asymptomatic liver enzyme elevations. In comparison with haloperidol, the adverse events reported significantly more frequently with olanzapine in > or = 3.5% of patients were dry mouth, bodyweight gain and increased appetite and compared with risperidone, only bodyweight gain occurred significantly more frequently with olanzapine. The high acquisition cost of olanzapine is offset by reductions in other treatment costs (inpatient and/or outpatient services) of schizophrenia. Pharmacoeconomic analyses indicate that olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Compared with risperidone, olanzapine has also been reported to decrease overall treatment costs, despite the several-fold higher daily acquisition cost of the drug. Olanzapine treatment improves quality of life in patients with schizophrenia and related psychoses to a greater extent than haloperidol, and to broadly the same extent as risperidone. CONCLUSIONS: Olanzapine demonstrated superior antipsychotic efficacy compared with haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-episode or treatment-resistant schizophrenia. The reduced risk of adverse events and therapeutic superiority compared with haloperidol and risperidone in the treatment of negative and depressive symptoms support the choice of olanzapine as a first-line option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

Risperidone in the treatment of acute schizophrenia

INTRODUCTION: Atypical antipsychotics have proven efficacy and tolerability in the treatment of schizophrenia. While a lot is known about maintenance treatment with atypical antipsychotics, less is known about their role in the management of acute psychotic decompensations. To evaluate the efficacy of the atypical antipsychotic risperidone, we conducted an open-label observational study among admissions to a secure unit. METHOD: Treatment with risperidone was offered to acutely psychotic schizophrenic patients with the requirement of a minimum score of > or =4 on 2 items of the PANSS positive symptoms subscale. Subjects were treated with 4 to 8 mg risperidone in divided doses (mean dose 5.7 +/- 1.5 mg/d). Benzodiazepines and anticholinergics were allowed as co-medications. Clinical Global Impression ratings and Positive and Negative Syndrome Scale ratings were obtained weekly for 4 weeks. RESULTS: Forty-eight subjects (25 males, 23 females; mean age 36.9 +/- 13.4 years, range 18 to 68 years) participated in this study. The mean duration of treatment was 13.4 +/- 9.7 days (range 1 to 31 days). Risperidone was well tolerated, and 26 (54%) patients completed the study. Reasons for discontinuation were need of intramuscular antipsychotic medication (8 subjects), switch to a different antipsychotic (11 subjects), side effects (1 subject), and noncompliance (2 subjects). Treatment with risperidone reduced the mean CGI score from 5.9 to 4.8 (P < 0.001). Likewise, the total PANSS score improved from 110.9 to 86.0 (P < 0.001) with similar reductions in all subscales. DISCUSSION: Our results demonstrate that risperidone is an effective and well-tolerated medication for the pharmacologic management of acutely psychotic schizophrenic subjects.     

The efficacy and safety of risperidone for the treatment of geriatric psychosis.

Risperidone is an atypical antipsychotic drug which has been suggested to be beneficial for the treatment of elderly patients with psychotic symptoms. In this study, we assessed the short-term efficacy and the safety of risperidone in geropsychiatric inpatients with psychotic symptoms. The sample population included 110 elderly inpatients with psychotic disorders. Assessment for drug efficacy using the Brief Psychiatric Rating Scale, Sandoz Clinical Assessment-Geriatric scale, and Clinical Global Impression scale was conducted at baseline and also at 4 weeks subsequent to risperidone treatment commencement. Subsequent to commencing risperidone treatment, 80 patients completed a 4-week therapeutic evaluation. Seventy (87.5%) of the 80 patients experienced mild to substantial improvement using the Clinical Global Impression scale. Adverse effects were monitored in all 110 patients. The most commonly detected adverse effects were weakness of legs or walking problems (43/110; 39.1%) and dizziness (32/110; 29.1%). Peripheral edema was noted in 18 (16.4%) patients. Risperidone, in low doses, appeared to have been effective in this sample of patients older than 65 years with psychotic symptoms. The mean dose (2.1 +/- SD 1.4 mg/day) applied was lower then that suggested for young patients and was related to the each specific patient diagnosis. Peripheral edema and walking problems were commonly observed adverse effects for these elderly patients, such problems having not been seen to the same extent in previous studies of young patients.     

A review of the efficacy, tolerability and safety of sertindole in clinical trials

Sertindole is a non-sedating atypical antipsychotic agent with high selectivity for dopaminergic neurons in the mesolimbic system. In pivotal clinical trials, sertindole has demonstrated significantly greater efficacy than placebo against both the positive and negative symptoms of schizophrenia. In addition, sertindole has had at least similar efficacy to haloperidol and risperidone against positive symptoms, and significantly greater efficacy than haloperidol and risperidone against negative symptoms. The incidence of extrapyramidal symptom (EPS)-related adverse events and the rate of medication used to treat EPS in patients receiving clinically effective doses of sertindole in clinical trials were similar to those observed in placebo recipients and significantly less than those in haloperidol recipients. The incidence of QTc interval prolongation of 500 ms or greater with therapeutic dosages of sertindole has also been low. In general, sertindole has been well tolerated in clinical trials. Unlike other antipsychotic agents, sertindole has not been associated with cognitive impairment, and can actually improve cognitive function. Observational studies have shown that the efficacy and tolerability of sertindole observed in the clinical trial situation are emulated in a naturalistic setting. Large cohort analyses (N > 8000) have shown that all-cause and cardiovascular mortality is no greater with sertindole than with risperidone or olanzapine.     

Amisulpride: a review of its use in the management of schizophrenia

Amisulpride (Solian), a substituted benzamide derivative, is a second-generation antipsychotic that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. High dosages preferentially antagonise postsynaptic D2/D3 receptors, resulting in reduced dopamine transmission, and low dosages preferentially block presynaptic D2/D3 receptors, resulting in enhanced dopamine transmission. Amisulpride (200-1200 mg/day) was at least as effective as haloperidol and as effective as risperidone or olanzapine, in studies of up to 1 year in patients with schizophrenia manifesting predominantly positive symptoms. Amisulpride (50-300 mg/day) was significantly more effective than placebo in studies of up to 6 months in patients manifesting predominantly negative symptoms. Quality of life was also improved significantly more in patients receiving amisulpride than in those receiving haloperidol in 4- and 12-month studies in patients with predominantly mixed symptoms. Amisulpride was generally well tolerated in clinical trials. In patients with predominantly positive symptoms, amisulpride appeared to be better tolerated than haloperidol and was tolerated as well as risperidone and olanzapine. The incidence of extrapyramidal adverse effects with amisulpride was lower than with haloperidol but was generally similar to risperidone or olanzapine. Weight gain with amisulpride was less than that with risperidone or olanzapine and, unlike these agents, amisulpride does not seem to be associated with diabetogenic effects. Plasma prolactin levels are increased during amisulpride therapy and amenorrhoea occurs in about 4% of women. The incidence of adverse events with low dosages of amisulpride (< or = 300 mg/day) in patients with predominantly negative symptoms was similar to that observed with placebo. In conclusion, oral amisulpride (200-1200 mg/day) is at least as effective as haloperidol, and as effective as risperidone or olanzapine, in the treatment of patients with schizophrenia manifesting predominantly positive symptoms. In the treatment of patients manifesting predominantly negative symptoms, low dosages of amisulpride (50-300 mg/day) are significantly more effective than placebo. Amisulpride appears to be better tolerated than haloperidol, causing a lower incidence of extrapyramidal adverse effects and an improved quality of life. Compared with risperidone or olanzapine, amisulpride is more likely to cause hyperprolactinaemia, but has a lower propensity to cause weight gain and does not seem to be associated with diabetogenic effects. Thus, amisulpride is an effective and well tolerated option for the first-line treatment of patients with acute schizophrenia as well as for those requiring long-term maintenance therapy.     

Spotlight on ziprasidone in schizophrenia and schizoaffective disorder

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin levels. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. CONCLUSIONS: Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.     

Risperidone: clinical safety and efficacy in schizophrenia.

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.     

Prolactin levels in male schizophrenic patients treated with risperidone and haloperidol: a double-blind and randomized study

Rationale There are few data from systematic, double-blind clinical trials that have compared the effect of the typical and the atypical antipsychotics on serum prolactin (PRL) levels in patients with schizophrenia.Objectives The goal of this study was to compare the effect of risperidone and haloperidol on serum PRL and investigate the relationship between serum PRL levels and clinical response in patients with schizophrenia.Methods Seventy-eight inpatients with a diagnosis of schizophrenia (according to DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol after a 2-week washout period, using a randomized, double-blind design. Clinical efficacy was determined using the positive and negative syndrome scale (PANSS). Their serum PRL was assayed by means of radioimmunometric assay (RIA) between pre-treatment and post-treatment, and compared with 30 sex-matched and age-matched normal subjects.Results Both risperidone and haloperidol treatment significantly increased serum PRL levels in drug-free chronic schizophrenia patients (both P<0.001). Hyperprolactinemia induced by risperidone 6 mg/kg was comparable to levels produced by haloperidol 20 mg/day. Considering dose-adjusted serum PRL levels, risperidone treatment induced a significant elevation of PRL levels compared with haloperidol treatment at the haloperidol equivalent (P<0.001). Change in PRL levels at pre-treatment and post-treatment were related to positive symptom improvement seen in the risperidone group (r=0.51, P=0.016), but not in the haloperidol group (P>0.05). Female patients showed both a higher baseline and post-treatment PRL level and a greater increase in PRL than men (all P<0.05).Conclusions Risperidone is associated with a robust effect on prolactin secretion in contrast to the conventional antipsychotic haloperidol. Prolactin monitoring during risperidone treatment should be performed.     

Comparative behavioural effects of typical and atypical antipsychotic drugs in rhesus monkey

Behavioural effects of typical and atypical antipsychotic agents were compared in unrestrained rhesus monkey (Macaca mulatta) living in social colonies. The behaviours were categorized as social, solitary and abnormal. They were studied with the help of video cameras fixed in the observation chamber. The behavioural effects were recorded on videotape and analyzed for significant changes. Chlorpromazine (2.5-10 mg/kg, i.m.), haloperidol (0.01-0.04 mg/kg, i.m.), risperidone (0.05-0.2 mg/kg, p.o.) and clozapine (5-20 mg/kg, p.o.) induced significant alterations in parameters of social and solitary behaviour. Chlorpromazine produced a marked decrease in locomotor activity whereas haloperidol showed marked extrapyramidal effects. Risperidone produced minimal extrapyramidal effects and sedation compared to haloperidol and chlorpromazine. Clozapine had intermediate extrapyramidal effects similar to those of chlorpromazine but it produced hypersalivation and dose-related sedation. Thus, risperidone had advantages over the other antipsychotics used in this study because it did not produce salivation, had minimal extrapyramidal effects and caused less sedation. These antipsychotic drugs produced many behavioural effects in the rhesus monkey that were similar to their clinically observed effects. A study of behavioural effects in the monkey can thus be a useful predictive tool in the preclinical development of new antipsychotics.