Atypical Antipsychotic Risperidone Research Articles

P.3.043 Comparative effects of atypical antipsychotic on tardive dyskinesia and neurocognition: a 24-week randomized, single-blind, controlled study

Background: Since treatment approaches thought to be useful for mania are presumably suitable for hypomania as well, little systematic research has been done on the treatment of hypomanic episodes and their long-term outcome. As systematic trials have shown that the atypical antipsychotic risperidone may be effective and safe in the treatment of acute mania, we decided to conduct an open-label study of its effectiveness and tolerability in hypomania associated with bipolar II. Methods: Forty-four DSM-IV bipolar II patients with Young Mania Rating Scale (YMRS) scores above 7 were included and followed-up for 6 months. Efficacy was measured by means of the YMRS and the Clinical Global Impression for Bipolar Disorder (CGI-BD). Treatment-emergent depression was measured by the Hamilton Depression Rating Scale (HDRS-17), and the Udvalg for Kliniske Undersøgelser (UKU) subscale was used for neurological/extrapyramidal side-effects. Results: Thirty-four patients completed the trial. The mean dose of risperidone at endpoint was 2.8 mg/day. Last observation-carried-forward analysis showed significant reduction of YMRS scores from the first week of treatment, which continued until the endpoint (P<0.0001). At 6-month follow-up, 60% of patients were assymptomatic according to the CGI. The 32% who received risperidone in monotherapy seemed to respond equally well. Risperidone, as used in this study, appeared to be most protective against hypomanic than depressive recurrences. Nine patients (12%) had a depressive relapse during 6-month follow-up, one patient (2%) had an hypomanic relapse and another (2%) had both. No patients developed tardive dyskinesia during the duration of the study. Although most patients received risperidone in combination with standard mood-stabilizers, only three patients discontinued risperidone because of other side-effects. Limitations: In the absence of a placebo arm, it is uncertain to what extent the foregoing results could be ascribed to spontaneous remission of bipolar II disorder. Conclusions: Risperidone, either in combination with mood-stabilizers or alone was well-tolerated in bipolar II patients, who presented in a hypomanic state, and appeared efficacious. Further controlled research on the role of atypical antipsychotics in the treatment of less-than-manic forms of bipolar illness is warranted.

Generalization testing with atypical and typical antipsychotic drugs in rats trained to discriminate 5.0 mg/kg clozapine from vehicle in a two‐choice drug discrimination task

AbstractClozapine (CLZ) drug discrimination is used as a preclinical model to evaluate compounds for putative atypical antipsychotic properties. In rats, a 1.25 mg/kg CLZ training dose appears to have greater pharmacological specificity for atypical antipsychotic drugs than the traditional 5.0 mg/kg CLZ training dose; however, methodological differences among studies have precluded a direct comparison between these training doses. In the present study, rats were trained to discriminate a 5.0 mg/kg CLZ dose from vehicle in a two‐choice drug discrimination task using methods similar to those in a previous study from our laboratory that used a 1.25 mg/kg CLZ training dose. Clozapine produced full substitution (≥80% CLZ‐lever responding) for itself at the training dose (5.0 mg/kg). The atypical antipsychotics olanzapine, quetiapine, and ziprasidone also produced full substitution for 5.0 mg/kg CLZ, whereas the atypical antipsychotics risperidone and sertindole produced partial substitution (≥60% CLZ‐lever responding). The typical antipsychotic, thioridazine, produced full substitution for the 5.0 mg/kg CLZ training dose, but the typical antipsychotics chlorpromazine, fluphenazine, and haloperidol failed to substitute for clozapine. In a subgroup of 1.25 mg/kg CLZ‐trained rats, ziprasidone produced strong partial substitution (73.0 % CLZ‐lever responding) for the 1.25 mg/kg CLZ training dose. Based on these findings, some atypical antipsychotic drugs (i.e., quetiapine and ziprasidone) produce full substitution only for the 5.0 mg/kg CLZ training dose, whereas other atypical antipsychotic drugs (i.e., sertindole and risperidone) produce full substitution only for the 1.25 mg/kg CLZ training dose. Thus, both of these training doses are important for the screening of putative atypical antipsychotic drugs with the clozapine drug discrimination assay. Drug Dev. Res. 64:55–65, 2005. © 2005 Wiley‐Liss, Inc.

P.3.127 A randomised, double-blind clinical trial comparing treatment with amisulpride or risperidone for six weeks in elderly patients with schizophrenia

Background: Published case reports describe apparent induction or exacerbation of manic-like symptoms during treatment with the atypical antipsychotics olanzapine and risperidone. To date, such reports are from uncontrolled clinical experience and therefore cannot clarify whether the atypical antipsychotics caused such manic-like states or simply failed to prevent them. Presumably, bipolar patients would be at increased risk for this putative adverse event. Therefore, we evaluated the potential of olanzapine to exacerbate symptoms of mania compared to placebo during treatment of bipolar mania. Methods: Two inpatient, double-blind, randomized trials investigating the efficacy of olanzapine 5–20 mg daily versus placebo for the treatment of acute mania were combined. Two hundred and fifty-four subjects participated (placebo n=129; olanzapine n=125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to 3 weeks, categorical comparison of olanzapine and placebo groups was made for any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). Results: The percentage of subjects with exacerbation at endpoint were: any worsening, placebo 37.7%, olanzapine 21.8% (P=0.005); ≥10% worsening, placebo 24.6%, olanzapine 14.5% (P=0.039); ≥20% worsening, placebo 15.6%, olanzapine 8.1% (P=0.064). Conclusion: Mania rating scores worsened for some patients during olanzapine therapy. However, this was significantly less common with olanzapine than with placebo. These controlled data suggest that clinical case reports of occurrence of ‘mania’ during treatment with olanzapine, and possibly those with other atypical antipsychotics, reflect exacerbation in the natural history of bipolar illness, rather than an adverse pharmacological effect. Limitations: Post-hoc analysis of pooled data from two different studies.

Erotomania

Erotomania is generally classified as a delusional disorder in contemporary classification systems (DSM-IV and ICD-10). The incidence of erotomania is not known, but that of delusional disorder in general has been reported as approximately 15 cases per 100,000 of the population per year, with a female : male ratio of 3 : 1. Both primary and secondary types of erotomania have been identified, the latter being associated with evidence of an aetiologically significant organic or psychiatric condition. The aetiology of primary erotomania is not yet fully understood, but neuroimaging, genetic studies and findings from evolutionary psychopathology hold considerable promise for a deeper and broader understanding of this condition. The initial management of secondary erotomania focuses on treating the underlying organic or psychiatric illness. The management of primary and secondary erotomania involves a combination of pharmacological treatments, psychosocial interventions and risk management strategies. In the past, the antipsychotic medication pimozide was commonly used, at least in certain countries (such as the US and Canada), despite a paucity of systematic studies of its use in this disorder. In recent years, there have been reports of positive therapeutic outcomes with atypical antipsychotics (risperidone, clozapine), which, as a result of their improved tolerability over older agents such as pimozide, will hopefully enhance patient acceptability and, thereby, improve clinical outcome. Despite this advance, there is still a strong need for controlled clinical trials of therapeutic strategies for primary erotomania and related syndromes.

P.3.129 Aripiprazole for relapse prevention in bipolar disorder: a 26-week placebo-controlled study

Background: Published case reports describe apparent induction or exacerbation of manic-like symptoms during treatment with the atypical antipsychotics olanzapine and risperidone. To date, such reports are from uncontrolled clinical experience and therefore cannot clarify whether the atypical antipsychotics caused such manic-like states or simply failed to prevent them. Presumably, bipolar patients would be at increased risk for this putative adverse event. Therefore, we evaluated the potential of olanzapine to exacerbate symptoms of mania compared to placebo during treatment of bipolar mania. Methods: Two inpatient, double-blind, randomized trials investigating the efficacy of olanzapine 5–20 mg daily versus placebo for the treatment of acute mania were combined. Two hundred and fifty-four subjects participated (placebo n=129; olanzapine n=125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to 3 weeks, categorical comparison of olanzapine and placebo groups was made for any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). Results: The percentage of subjects with exacerbation at endpoint were: any worsening, placebo 37.7%, olanzapine 21.8% (P=0.005); ≥10% worsening, placebo 24.6%, olanzapine 14.5% (P=0.039); ≥20% worsening, placebo 15.6%, olanzapine 8.1% (P=0.064). Conclusion: Mania rating scores worsened for some patients during olanzapine therapy. However, this was significantly less common with olanzapine than with placebo. These controlled data suggest that clinical case reports of occurrence of ‘mania’ during treatment with olanzapine, and possibly those with other atypical antipsychotics, reflect exacerbation in the natural history of bipolar illness, rather than an adverse pharmacological effect. Limitations: Post-hoc analysis of pooled data from two different studies.

Comparing efficacy of first-line atypical antipsychotics: no evidence of differential efficacy between risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole

ObjectiveTo evaluate the comparative efficacy of the first-line atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.MethodsWe reviewed published short-term, randomised, controlled clinical trials of first-line atypical antipsychotics in the treatment of schizophrenia or schizoaffective disorder that used the Positive and Negative Syndrome Scale to assess efficacy. We used a combined overview analysis to compare the extent of improvement in global symptoms and positive and negative symptoms. We did not analyse adverse event data.ResultsAlthough we found considerable variation in the degree of improvement with a particular atypical antipsychotic across different studies, the range and average improvement were similar among all first-line atypicals for all efficacy parameters considered. Dosage was a critical determinant of efficacy, although the most effective dose of each agent varied across studies. There were insufficient data for ziprasidone and aripiprazole to allow their inclusion in the formal overview comparison.ConclusionDespite confounding and methodological limitations, the data we reviewed do not support assertions of differential efficacy between the first-line atypical antipsychotics. Additional controlled comparative studies of the atypical antipsychotics should be of particular interest.

Abnormalities in visually guided saccades suggest corticofugal dysregulation in never-treated schizophrenia

Previous studies have reported intact visually guided saccades in schizophrenia, but these are limited by potential acute and long-term pharmacological treatment effects, small sample sizes, and a failure to follow patients over time. Visually guided saccades were examined in 44 antipsychotic-naive patients experiencing their first episode of schizophrenia prior to treatment and again after 6, 26, and 52 weeks of antipsychotic treatment. Thirty-nine matched healthy individuals were followed over the same period. Before treatment, patients showed faster saccade latencies to unpredictable visual targets, suggesting reduced inhibitory regulation of brainstem saccade generators by neocortical attentional systems. Risperidone treatment reduced this deficit, suggesting a facilitation of attentional function, but haloperidol treatment did not. However, there was also a modest decline in saccade accuracy after risperidone treatment. The ability to sustain fixation of static central and peripheral targets was unimpaired before and after treatment. These findings provide evidence for impairments in neocortical attentional systems that cause reduced corticofugal regulation of brainstem systems in schizophrenia. This dysfunction appears to be minimized by the atypical antipsychotic risperidone but at the cost of a subtle reduction in saccade accuracy, possibly mediated via adverse effects on cerebellar vermis function.

Selective prescribing of atypical antipsychotics

The aim of the study was to investigate whether the most recent introduced atypical antipsychotics olanzapine and risperidone were preferentially prescribed to patients susceptible to develop extrapyramidal side effects (EPS) and those not responding adequately to typical antipsychotics. Data were obtained from the Dutch PHARMO system that includes complete medication and hospital admission records of 675 000 residents of 14 Dutch cities. A total number of 129 new users of olanzapine and 142 new users of risperidone as well as 507 new users of typical antipsychotic drugs were identified from our database in the period of 1996-1998. The prevalence of markers of EPS, therapy resistance and therapy non-compliance were assessed in the period of 1 year prior to a new start of an antipsychotic. New use of olanzapine and risperidone was significantly associated with previous use of other antipsychotics (odds ratio 4.0, 95%CI: 2.5-6.7 and odds ratio 3.0, 95%CI: 2.0-4.7, respectively). New use of olanzapine and risperidone was also associated with previous use of anticholinergic drugs compared to users of typical antipsychotics (over three and two times more, respectively). This effect diminished when adjusted for previous use of antipsychotics. In particular olanzapine and also risperidone were selectively prescribed to patients formerly treated with other antipsychotics and to those susceptible for EPS. If not recognised or controlled for, observational studies comparing different antipsychotic drugs may produce biased results on efficacy or frequency of side effects for the different types of antipsychotics.

Effects of Changing From Typical to Atypical Antipsychotic Drugs on Subjective Sleep Quality in Patients With Schizophrenia in a Japanese Population

To investigate the effects of the atypical antipsychotic drugs risperidone, olanzapine, quetiapine, and perospirone on the subjective quality of sleep in patients with schizophrenia. Subjects were 92 inpatients (mean age = 59.9 years) who had been receiving treatment with conventional antipsychotic drugs and who met the DSM-IV criteria for schizophrenia. Subjects were randomly assigned to receive 1 of 4 atypical antipsychotic drugs (olanzapine, perospirone, quetiapine, and risperidone). Subjective sleep quality and psychopathology were assessed twice: at baseline and 8 weeks after switching. Data were collected from June 2001 to December 2001. Subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI), and psychopathology was measured by the Positive and Negative Syndrome Scale (PANSS). Subjective sleep quality as assessed by the PSQI was significantly improved with administration of olanzapine, risperidone, or quetiapine, but not with perospirone, in comparison with conventional antipsychotic drugs. Multiple regression analysis revealed that the improvement of sleep quality with administration of atypical antipsychotic drugs was predicted by poor sleep quality at baseline. In addition, improvement of sleep quality was significantly correlated with improvement of negative symptoms as assessed by the PANSS. These results demonstrated that atypical antipsychotic drugs improved subjective quality of sleep in patients with schizophrenia compared with conventional antipsychotic drugs, suggesting that the marked potency of serotonin-2 receptor blockade in atypical antipsychotic drugs may be involved in the mechanism of this improvement. These improvements were correlated with improvement of negative symptoms.

Psychotropic Effects of COX-2 Inhibitors - A Possible New Approach for the Treatment of Psychiatric Disorders

Cyclooxygenase-2 (COX-2)--constitutively expressed in the CNS--is suggested to have an important functional role in the CNS. COX-2 interacts with neurotransmitters such as acetylcholine, serotonin, and glutamate, but is also involved in the regulation of immune system and in inflammation in the central nervous system (CNS) via effects of prostaglandins, in particular prostaglandin E (2). Recently, a role for the new generation of selective COX-2 inhibitors in the treatment of psychiatric disorders is discussed. Until now, COX-2 inhibitors have failed to show therapeutic effects in Alzheimer's disease, but studies from basic research point to a possible effect on cognition. A clinical effect of the COX-2 inhibitor celecoxib on cognition was observed in schizophrenic patients. The therapeutic effect of celecoxib add-on treatment to the atypical antipsychotic risperidone, however, is not restricted to cognition. A general effect on symptoms of schizophrenia was observed, which supports the view that an immunological/inflammatory process is involved in the pathogenesis of schizophrenia. In depression, however, signs of inflammation have been described since many years. Although results of clinical studies with COX-2 inhibitors in depression are still lacking, clinical improvement of a depressive syndrome has been observed in patients, who have been treated with rofecoxib due to other indications. These preliminary clinical data are encouraging for therapeutic effects of the selective COX-2 inhibitors in psychiatric disorders, although these effects have to be confirmed in bigger clinical studies.

Atypical antipsychotic medications for borderline personality disorder: What’s the story?

Atypical antipsychotic medications have been approved for treatment of schizophrenia and broad efficacy has led to trials for other illnesses. For borderline personality disorder (BPD), traditional antipsychotics had been demonstrated to reduce symptoms, but were not well tolerated. This paper reviews the new data emerging from trials assessing safety and efficacy of the atypical antipsychotic medications risperidone, olanzapine, and quetiapine (studies of ziprasidone and aripiprazole have not been published). To date, the results of studies with atypical antipsychotics have shown reduction of symptoms from across a broad number of domains. Also, early placebo-controlled trials show an advantage for these agents. Taken together, these new studies are pointing to a positive direction and offer hope for the treatment of BPD.

The use of risperidone among individuals with mental retardation: clinically supported or not?

Since their introduction, antipsychotic medications have been used widely to treat conditions other than psychiatric disorders, especially among individuals with mental retardation. Researchers have shown that the prevalence rates of psychotropic medication prescriptions among this population are extremely high. Given the limited empirical data to support the use of psychotropic medications, specifically antipsychotics, among individuals with mental retardation, this trend is a cause for concern. This review was undertaken in an effort to summarize the available studies regarding the use of the atypical antipsychotic drug risperidone among individuals with mental retardation and provide a resource for clinicians, care givers, and parents. Based on the results of this review, the effectiveness of risperidone in targeting psychopathology and challenging behaviors for individuals with mental retardation is questionable at present.

Lower Mortality in Geriatric Patients Receiving Risperidone and Olanzapine Versus Haloperidol: Preliminary Analysis of Retrospective Data

<h3>Objective</h3> The authors examined the mortality rate in geriatric patients receiving either haloperidol or atypical antipsychotics. <h3>Methods</h3> Authors tracked mortality over a 2-year period in patients age 65 years or older receiving haloperidol (N=299) or the atypical antipsychotics risperidone or olanzapine (N= 1,254). <h3>Results</h3> Sixty-four patients in the haloperidol group (21.4%) and 61 patients in the atypical group (4.75%) died during the 2-year study period. The difference was statistically significant. <h3>Conclusions</h3> The findings suggest that mortality in elderly patients receiving haloperidol is significantly higher than in those receiving the atypical antipsychotics risperidone or olanzapine. Authors discuss possible causal mechanisms.

Advances in Therapeutic Drug Monitoring of Atypical Antipsychotic Drugs

The introduction in clinical practice of new antipsychotic drugs neurologically safer and with a broader spectrum of efficacy than “classical” neuroleptics has brought about significant improvement in the therapy of schizophrenic patients. These second-generation antipsychotics usually called “atypical” antipsychotics, have several therapeutical features in common, such as their effectiveness against the negative symptoms of schizophrenia and the advantage of not causing severe extrapyramidal symptoms and hyperprolactinemia. The therapeutic drug monitoring of patients treated with atypical antipsychotics is however, still advisable. In many cases, it can avoid the onset of side and toxic effects due to high plasma levels of the drug caused by overdose or interactions with other drugs. Furthermore, monitoring can significantly improve the patients compliance, thus leading to higher treatment efficacy. The pharmacological properties of the most widely used atypical antipsychotics (clozapine, olanzapine, risperidone and quetiapine) will be treated herein with particular attention paid to metabolism, side effects and pharmacokinetics. The analytical methods suitable for the therapeutical drug monitoring of these drugs will also be discussed, in terms of sensitivity, selectivity and usefulness in clinical settings. Other recent atypical agents (ziprasidone, aripiprazole, iloperidone, sertindole and zotepine) will be described as well.

Risperidone in the Treatment of Acute Schizophrenia

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. 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. 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. Our results demonstrate that risperidone is an effective and well-tolerated medication for the pharmacologic management of acutely psychotic schizophrenic subjects.

Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats

Previously we reported that chronic exposure to haloperidol (HAL), but not the atypical antipsychotics risperidone (RISP) or clozapine (CLOZ), resulted in reductions in brain choline acetyltransferase (ChAT) immunoreactivity and impaired water maze task performance in rats. In the present study, we compared the effects of these antipsychotic drugs on the expression of nerve growth factor (NGF) as well ChAT the in the rat cortex and nucleus basalis of Meynert (NBM) in an effort to determine the underlying mechanism for the differential drug effects observed previously. We also evaluated the effects of these compounds in a crossover design to evaluate specific neurochemical consequences of switching between typical and atypical antipsychotics, a common practice observed in the clinical setting. Male Wistar rats (250–300 g) were exposed to HAL (2.0 mg/kg/day), RISP (2.5 mg/kg/day), or CLOZ (20 mg/kg/day) for 45 days or a pre-treatment regimen consisting of administering either RISP/HAL (i.e., RISP followed by HAL) or CLOZ/HAL, or a post-treatment regimen consisting of administering: HAL/RISP or HAL/CLOZ. The duration of each treatment in the crossover study was also 45 days. NGF and ChAT immunoreactivity were measured by quantitative immunohistochemistry in some sub-cerebral cortical regions and NBM after drug exposures. NGF protein was also measured by an enzyme-linked ImmunoSorbent assay (ELISA) in rat sensorimotor cortex. The results indicated that HAL (but not RISP or CLOZ) significantly reduced NGF levels in some sub-cortical regions and ChAT immunoreactivity in both cortex and NBM. However, pre-treatment with CLOZ prevented the HAL-associated decreases in NGF and ChAT, while post-treatment with either RISP or CLOZ (i.e., after the administration of HAL) appeared to restore NGF and ChAT to control levels. These data indicate that antipsychotic drugs exert dissimilar effects on the levels of NGF and ChAT in the brain, which may contribute to their differential effects on cognitive function. The crossover data further suggest that certain atypical antipsychotic drugs (e.g., clozapine) may have the potential to prevent or reverse the deleterious effects of HAL on important neurochemical substrates of cognitive function.

Effect of switching to atypical antipsychotics on memory in patients with chronic schizophrenia

While the usefulness of atypical antipsychotics for improving cognitive function has been proven, the specific effects of these drugs are still unknown. The objective of this study was to investigate changes of the immediate memory and verbal working memory in patients with chronic schizophrenia after switching to one of four atypical antipsychotic agents and cessation of anticholinergic therapy. The subjects included 77 schizophrenic patients who were treated primarily with typical antipsychotics. Treatment was randomly switched to one of four atypical antipsychotics (olanzapine, perospirone, quetiapine, or risperidone) over a 4-week period, and then the drug was continued for another 4 weeks while the patient was taken off anticholinergics. The immediate memory, verbal working memory, and symptoms were evaluated. Significant improvement of immediate memory was only seen with olanzapine and risperidone. Improvement was also seen after switching to perospirone, but immediate memory worsened after treatment with this anticholinergic drug was discontinued. Deterioration was seen after switching to quetiapine, but immediate memory improved and reached the previous level after treatment with anticholinergic drugs was discontinued. Significant improvement of the verbal working memory was only seen during risperidone administration. The findings suggested that switching chronic schizophrenic patients to atypical antipsychotics can improve both the immediate memory and the verbal working memory when risperidone is used, while improvement of immediate memory can be expected with olanzapine. From the viewpoint of improving the memory, quetiapine should not be administered concomitantly with anticholinergic drugs, and caution should be exercised when discontinuing anticholinergic drugs during treatment with perospirone.

Acute Treatment of Psychotic Agitation

Standard treatment for acute psychotic agitation often involves intramuscular administration of the benzodiazepine lorazepam and the antipsychotic haloperidol. This study compared the efficacy and safety of oral treatment with the atypical antipsychotic risperidone plus lorazepam with those of standard intramuscular treatment. We hypothesized that the efficacy and speed of action of both treatments would be similar. In a prospective, parallel-group, randomized, rater-blinded noninferiority study conducted at 24 sites in the United States, 162 patients exhibiting agitation associated with active psychosis were randomly assigned to receive either oral treatment with 2 mg of risperidone plus 2 mg of lorazepam (N = 83) or intramuscular treatment with 5 mg of haloperidol plus 2 mg of lorazepam (N = 79). The change scores on a 5-item acute-agitation cluster from the Positive and Negative Syndrome Scale (hallucinatory behavior, excitement, hostility, uncooperativeness, and poor impulse control) were the main outcome measure. The study was conducted from January 8 to August 8, 2001. Mean acute-agitation cluster scores were similar in the 2 groups at baseline. Mean score improvements at 30, 60, and 120 minutes after dosing were significant at each timepoint in both groups (p <.0001) and were similar in both groups (p >.05). Both treatments were well tolerated. A single oral dose of risperidone plus lorazepam was as effective as parenterally administered haloperidol plus lorazepam for the rapid control of agitation and psychosis. These findings suggest that this oral regimen is an acceptable alternative to the current intramuscular treatment for acute psychotic agitation.

Sleep in schizophrenia patients and the effects of antipsychotic drugs

Insomnia is a common feature in schizophrenia. However, it seldom is the predominant complaint. Nevertheless, severe insomnia is often seen during exacerbations of schizophrenia, and may actually precede the appearance of other symptoms of relapse. The sleep disturbances of either never-medicated or previously treated schizophrenia patients are characterized by a sleep-onset and maintenance insomnia. In addition, stage 4 sleep, slow wave sleep (stages 3 and 4), non-REM (NREM) sleep in minutes and REM latency are decreased. The atypical antipsychotics olanzapine, risperidone, and clozapine significantly increase total sleep time and stage 2 sleep. Moreover, olanzapine and risperidone enhance slow wave sleep. On the other hand, the typical antipsychotics haloperidol, thiothixene, and flupentixol significantly reduce stage 2 sleep latency and increase sleep efficiency. Future research should address: (1) the sleep patterns in subtypes of schizophrenia patients; (2) the role of neurotransmitters other than dopamine in the disruption of sleep in schizophrenia; (3) the functional alterations in CNS areas related to the pathophysiology of schizophrenia during NREM sleep and REM sleep (brain imaging studies); (4) the short-term, intermediate-term, and long-term effects of atypical antisychotics on sleep variables.

Cabergoline treatment of risperidone-induced hyperprolactinemia: a pilot study.

D(2) blockers, including the atypical antipsychotic risperidone, induce hyper-prolactinemia in a significant number of patients treated. The endocrine and sexual side effects related to hyperprolactinemia significantly impair tolerability and compliance in patients, including those with a good response to risperidone. This pilot study aimed to evaluate the efficacy and tolerability of a low dose of cabergoline, a D(2) agonist, in the treatment of risperidone-induced hyperprolactinemia. Nineteen male and female DSM-IV-defined schizophrenic patients who were clinical responders to risperidone but were suffering from symptomatic hyperprolactinemia were treated with cabergoline, 0.125 to 0.250 mg/week for 8 weeks. Plasma prolactin level was assessed at baseline and at the end of the study. Data were collected from January 2002 to April 2003. After cabergoline treatment, the mean decrease in plasma prolactin levels was statistically significant (p <.05) for the total sample, and 11 patients showed remission of clinical signs with prolactin values within the normal range. No side effect was observed or reported, and the patients' psychopathology was unchanged. Results suggest that low-dose cabergoline treatment of risperidone-induced hyperprolactinemia may be safe and clinically effective in a relevant number of patients.