Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term,placebo-controlled trials

Aripiprazole is a novel antipsychotic with a unique mechanism of action. Presented here is a pooled analysis of safety and tolerability data from all completed short-term, placebo-controlled trials in schizophrenia from the aripiprazole clinical development program. Data were analyzed from five 4- to 6-week double-blind multicenter studies of patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder randomized to aripiprazole (n=932), placebo (n=416), or haloperidol (n=201). Daily aripiprazole doses ranged from 2 to 30 mg. Safety assessments included adverse event (AE) reports, EPS scales, ECGs, weight, and prolactin, glucose and cholesterol levels. Aripiprazole was well tolerated, with similar AE incidence rates to placebo, and lower rates than haloperidol for akathisia, extrapyramidal syndrome and somnolence. Objective EPS assessments demonstrated no significant differences between aripiprazole and placebo on Simpson-Angus Scale (SAS) scores, no dose-dependent effects on Barnes Akathisia scores, and significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores from baseline vs. placebo (p相似文献   

Aripiprazole: a new atypical antipsychotic with a different pharmacological mechanism

Aripiprazole is a new atypical antipsychotic with a mode of action that is distinct from currently available antipsychotic drugs. In phase III comparative clinical studies, aripiprazole 15–30 mg/day was at least as effective as haloperidol and risperidone in short term treatment of acute exacerbation of schizophrenia but superior to haloperidol in long term maintenance therapy. Consistent with an atypical profile, aripiprazole is effective against positive, negative and cognitive symptoms of schizophrenia and has a favourable side effect profile with the incidence of extrapyramidal symptoms (EPS) comparable to placebo. It is also devoid of side effects such as clinically significant hyperprolactinaemia, hypercholesterolaemia and cardiotoxicity, and has a low propensity for weight gain. Symptom relief is achieved without significant sedation. These clinical data suggest its usefulness in psychosocial rehabilitation, as well as in long-term prevention of schizophrenic relapse. Recent results from a multicentre, open-label study in a general psychiatric setting provide the first evidence that aripiprazole is also effective under naturalistic conditions. However, only post-marketing experience will show whether the positive results of these controlled trials can be replicated in everyday practice.     

A review of aripiprazole in the treatment of patients with schizophrenia or bipolar I disorder

Aripiprazole has been approved by regulatory agencies for the treatment of schizophrenia and bipolar I disorder. Although it is a dopamine partial agonist, it also has substantial binding affinity for the serotonin 5HT2A receptor. Several double-blind randomized clinical trials have established the efficacy and tolerability of aripiprazole within the dose range of 10–30 mg/day for schizophrenia, and 15–30 mg/day for manic or mixed states associated with bipolar I disorder. Relatively few comparative trials with other second-generation antipsychotics have been published for schizophrenia, with none available for bipolar disorder. The evidence so far suggests that in terms of efficacy for schizophrenia, aripiprazole is superior to placebo and haloperidol (long term), similar to perphenazine and risperidone, and inferior to olanzapine. Its tolerability profile in patients with schizophrenia appears superior to haloperidol, perphenazine, risperidone, and olanzapine. Efficacy in treating manic or mixed states was established in placebo-controlled trials. Among some patients with bipolar disorder, akathisia and gastrointestinal (GI) complaints can emerge at the start of treatment; however, the GI symptoms were time-limited in many instances. Appropriate dosing may also be important in individualizing therapy to improve tolerability, with lower starting doses becoming more important when adding to, or switching from, another antipsychotic. Aripiprazole appears to have a low propensity for weight gain, a favorable metabolic profile, and no association with hyperprolactinemia.     

Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial

OBJECTIVE: Hyperprolactinemia and associated side effects often occur with antipsychotics. The authors investigated the effect of adjunctive treatment with aripiprazole on hyperprolactinemia and psychopathology in patients with schizophrenia maintained with haloperidol. METHOD: Fifty-six patients with hyperprolactinemia taking haloperidol were enrolled. Haloperidol dose was fixed; aripiprazole was dosed at 15 mg/day for the first 4 weeks, then 30 mg/day for the following 4 weeks. Serum prolactin, haloperidol, and aripiprazole levels were measured. Symptoms and side effects were assessed with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms, Clinical Global Impression symptom scale, Simpson-Angus Rating Scale, and Barnes Akathisia Rating Scale at weeks 1, 2, 4, 6, and 8. RESULTS: Prolactin levels of patients receiving aripiprazole significantly decreased over time, demonstrating a significant time effect and a time-by-group interaction. In the aripiprazole group, 88.5% of patients at week 8 had prolactin levels normalize compared to 3.6% of patients receiving placebo. Among 11 female patients with menstrual disturbances randomly assigned to aripiprazole, seven patients regained menstruation during the study, whereas none receiving placebo did. Plasma levels of haloperidol were not significantly altered. No significant time effect and time-by-group interactions on BPRS, Scale for the Assessment of Negative Symptoms, and Simpson-Angus Rating Scale scores were noted. CONCLUSIONS: Adjunctive aripiprazole treatment reversed hyperprolactinemia in both sexes, resulting in reinstatement of menstruation in female patients, with no significant effects on psychopathology and extrapyramidal symptoms. Aripiprazole has higher affinity to dopamine D(2) receptors than haloperidol, which is the likely cause of this observation.     

阿立哌唑与氟哌啶醇治疗难治性精神分裂症的对照研究

目的比较阿立哌唑与氟哌啶醇治疗难治性精神分裂症的疗效。方法78例符合入组条件的难治性精神分裂症病人，随机分2组，分别应用阿立哌唑或氟哌啶醇治疗12用，应用阳性和阴性症状量表（PANSS）和刮反应量表（TESS）评定疗效和副反应。结果阿立哌唑组总有效率为61．54％，明显高于氟哌啶醇组的43．59％。2组间在PANSS总分，阴性症状量表分及一般病理症状量表分值方面的差异具有显著性意义（P〈0．01）。结论阿立哌唑对难治性精神分裂症的疗效优于氟哌啶醇，对阴性症状的效果尤其明显。     

阿立哌唑与氟哌啶醇治疗精神分裂症对照研究

目的:评价阿立哌唑与氟哌啶醇治疗精神分裂症的疗效及安全性。方法:阿立哌唑组50例,氟哌啶醇组48例,以阳性与阴性症状量表(PANSS)、临床疗效总评量表疾病严重程度(CGI-SI)、治疗中出现的症状量表(TESS)、锥体外系反应量表(RSESE)评定疗效及不良反应。疗程6周。结果:两组疗效相仿。阿立哌唑组PANSS阴性症状因子减分在治疗后4及6周显著优于氟哌啶醇组。阿立哌唑组不良反应显著较少。结论:阿立哌唑是一有效安全的抗精神病药。     

Role of aripiprazole in treating mood disorders

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of mood disorders. In the past few years, several atypical agents have received regulatory approval for use in mania. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers, such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Aripiprazole is a recently released antipsychotic medication that differs from other atypical antipsychotic agents by its mode of action as a dopamine D2 partial agonist. It is administered orally and has a long half-life. Randomized studies have demonstrated the efficacy of aripiprazole compared with placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, treatment of acute mania, and prevention of manic relapse in patients who responded to the drug during a manic episode. Further studies are ongoing in bipolar and unipolar depression. Aripiprazole is generally well tolerated compared with other antipsychotic medications, although commonly reported side effects include extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information regarding the comparative safety, efficacy and tolerability of aripiprazole in the treatment of affective disorders.     

Aripiprazole versus haloperidol treatment in early-stage schizophrenia

We conducted a secondary analysis of a completed study of the differential efficacy and side effects of aripiprazole versus haloperidol in early-stage schizophrenia (ESS), a subpopulation of patients which does not include first episode or chronic patients. A subpopulation of 360 individuals with ESS were identified from a randomized, multi-center, double-blind study of 1294 individuals with schizophrenia at different stages of illness who were randomized to treatment with aripiprazole (ESS = 237) or haloperidol (ESS = 123) for one year. The primary outcome measure was response rate based on a 50% reduction of Positive and Negative Syndrome Scale (PANSS) total scores. Secondary outcomes included several efficacy and safety measures, as well as treatment discontinuation. More individuals in the aripiprazole group (48%) than in the haloperidol group (28%; p < 0.01) completed the study. Response rates were greater in the aripiprazole group (38% [N = 91]) than in the haloperidol group (22% [N = 27]; p < 0.01). Aripiprazole was associated with fewer extrapyramidal side effects. ESS subjects in the haloperidol group were more likely than those in the aripiprazole group to discontinue the study drug due to an adverse event other than worsening illness (29% and 11%, respectively; p < 0.01), and efficacy differences were reduced by interventions to mitigate side effects (decreasing antipsychotic dose with or without adding antiparkinsonian medication). Aripiprazole has a favorable efficacy/safety profile in ESS and appeared to be superior to haloperidol on a number of efficacy and safety outcomes. However, excessive dosing of the antipsychotic medications, in particular haloperidol, may have played an important role in accounting for the differences between aripiprazole and haloperidol in this study.     

Acute effects of single‐dose aripiprazole and haloperidol on resting cerebral blood flow (rCBF) in the human brain

Antipsychotic drugs act on the dopaminergic system (first‐generation antipsychotics, FGA), but some also directly affect serotonergic function (second‐generation antipsychotics, SGA) in the brain. Short and long‐term effects of these drugs on brain physiology remain poorly understood. Moreover, it remains unclear whether any physiological effect in the brain may be different for FGAs and SGAs. Immediate (+3.30 h) and different effects of single‐dose FGA (haloperidol, 3 mg) and a SGA (aripiprazole, 10 mg) on resting cerebral blood flow (rCBF) were explored in the same 20 healthy volunteers using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T) in a placebo‐controlled, repeated measures design. Both antipsychotics increased striatal rCBF but the effect was greater after haloperidol. Both decreased frontal rCBF, and opposite effects of the drugs were observed in the temporal cortex (haloperidol decreased, aripiprazole increased rCBF) and in the posterior cingulate (haloperidol increased, aripiprazole decreased rCBF). Further increases were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics, in the motor cortex following haloperidol and in the occipital lobe the claustrum and the cerebellum after aripiprazole. Further decreases were observed in the parietal and occipital cortices after aripiprazole. This study suggests that early and different rCBF changes are evident following a single‐dose of FGA and SGA. The effects occur in healthy volunteers, thus may be independent from any underlying pathology, and in the same regions identified as structurally and functionally altered in schizophrenia, suggesting a possible relationship between antipsychotic‐induced rCBF changes and brain alterations in schizophrenia. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Aripiprazole treatment for patients with schizophrenia: from acute treatment to maintenance treatment

The most current treatment guidelines for schizophrenia recommend more than 1 year of maintenance therapy after the first psychotic episode, and more than 5 years of maintenance therapy after multiple psychotic episodes. Approximately two-thirds of such patients are known to relapse within 1 year and almost 90% of such patients may recur within 2 years. To maintain adequate consistent treatment, balancing the efficacy and safety/tolerability should be one of the most important clinical issues. In this respect, aripiprazole appears to be a good treatment option owing to its comparable efficacy, favorable safety and tolerability profile, including low incidence of parkinsonian symptoms, lack of prolactin elevation, decreased adrenergic and anticholinergic side effects, less weight gain and low incidence of metabolic syndrome. Hence this article aims to summarize the currently available clinical trial data of aripiprazole published from a number of large-scale randomized controlled studies, including a newer formulation of intramuscular injection as well as a once-monthly intramuscular depot formulation, to update knowledge of treatment options in patients with schizophrenia.     

Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder

BACKGROUND: Aripiprazole is an investigational agent for treating schizophrenia that has a novel pharmacologic profile. The present study investigated the efficacy, safety, and tolerability of aripiprazole and haloperidol compared with placebo. METHOD: A 4-week, double-blind, randomized study, conducted at 36 U.S. centers between July 1997 and June 1998, compared aripiprazole (15 mg/day, 30 mg/day) to placebo, with haloperidol (10 mg/day) as an active control. Fixed doses of each agent were administered from day 1 throughout the study. A total of 414 patients with a primary DSM-IV diagnosis of schizophrenia or schizoaffective disorder were randomized. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, PANSS-derived Brief Psychiatric Rating Scale (BPRS) core, Clinical Global Impressions (CGI)-Severity of Illness, and mean CGI-Improvement scores. Safety and tolerability evaluations included extrapyramidal symptoms (EPS), weight gain, serum prolactin level, and QTc interval. RESULTS: Both doses of aripiprazole and haloperidol, 10 mg, produced statistically significant (p < or = .05) improvements from baseline in PANSS total, PANSS positive, PANSS-derived BPRS core, and CGI-Severity scores and significantly lower CGI-Improvement scores at endpoint, compared with placebo. Aripiprazole, 15 mg, and haloperidol, 10 mg, significantly improved PANSS negative score compared with placebo. Both aripiprazole doses and haloperidol separated from placebo for PANSS total scores at week 2. Unlike haloperidol, aripiprazole was not associated with significant EPS or prolactin elevation at endpoint compared with placebo. There were no statistically significant differences in mean changes in body weight across the treatment groups versus placebo, and no patients receiving aripiprazole experienced clinically significant increases in QTc interval. CONCLUSION: Aripiprazole, effective against positive and negative symptoms, is a safe and well-tolerated potential treatment for schizophrenia and schizoaffective disorder.     

Efficacy of second-generation antipsychotics in the treatment of schizophrenia

Because of their broader spectrum of efficacy and lower risk of motor side effects, second-generation antipsychotics (SGAs) have largely supplanted first-generation neuroleptics in the treatment of psychotic disorders. There are few data, however, comparing the overall efficacy of the firstline SGAs (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) in the treatment of schizophrenia and schizoaffective disorder. To address this issue, two separate analyses were undertaken. First, all published short-term, randomized controlled clinical trials of these agents were reviewed, and efficacy data for total clinical improvement, positive symptom resolution, and negative symptom reduction compiled. Although the degree of improvement reported in these studies varied widely, there were no differences in efficacy of the drugs when averaged across all studies. Second, all randomized controlled clinical trials directly comparing two of these agents were reviewed. In direct comparison studies, there were no differences between the drugs on most parameters, and only minor and conflicting differences on remaining measures. Data thus far suggest that the first-line SGAs are of comparable efficacy in the treatment of schizophrenia and schizoaffective disorder.     

Efficacy of aripiprazole against hostility in schizophrenia and schizoaffective disorder: data from 5 double-blind studies

OBJECTIVE: The objective was to determine the effects of aripiprazole on hostility. METHOD: A total of 1476 patients diagnosed with DSM-IV schizophrenia or schizoaffective disorder were the subjects in 5 short-term, double-blind studies comparing aripiprazole with placebo; 3 of these studies also included a comparison with haloperidol. The studies were conducted between December 1993 and January 2001. The Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure in these studies. To determine the effect of aripiprazole on hostility, post hoc analyses of the hostility item from the PANSS were conducted for the first 4 weeks of treatment. RESULTS: Aripiprazole was superior to placebo and not significantly different from haloperidol in reducing hostility. CONCLUSION: Aripiprazole is an effective treatment for hostility in patients with schizophrenia or schizoaffective disorder.     

阿立哌唑治疗首发精神分裂症对照研究

目的:探讨阿立哌唑治疗首发精神分裂症的疗效和不良反应。方法:分别以阿立哌唑与氯丙嗪治疗首发精神分裂症各30例,采用阳性与阴性症状量表(PANSS)、副反应量表(TESS)评定疗效和不良反应。结果:阿立哌唑组有效率83.3%,显效率70.0%,氯丙嗪组有效率80.0%,显效率66.7%。两组疗效相仿,但阿立哌唑对阴性症状的改善优于氯丙嗪,且不良反应少于氯丙嗪。结论:阿立哌唑是一种安全有效的抗精神病药,尤其有助于阴性症状的改善。     

Two Cases of Hypersexuality Probably Associated with Aripiprazole

Sexual dysfunction is a common side effect in patients treated with antipsychotics but significant differences exist across different compounds. We report hypersexuality symptoms in two female patients with schizophrenia who were receiving treatment with aripiprazole. The patients experienced more frequent sexual desire and greater sexual preoccupation after taking aripiprazole. We discuss the potential neuro-chemical mechanisms for this and argue that aripiprazole''s unique pharmacological profile, partial agonism with high affinity at dopamine D2-receptor, may have contributed to the development of these symptoms.     

阿立哌唑治疗精神分裂症阴性症状Meta分析

目的探讨阿立哌唑与其他抗精神病药治疗精神分裂症阴性症状的疗效差异。方法用Meta分析对24项阿立哌唑与其他抗精神病药治疗精神分裂症阴性症状文章进行再分析,评价其合并效应量大小和综合显著性检验。结果阿立哌唑治疗前后的自身对照,提示阿立哌唑治疗精神分裂症阴性症状疗效明显,效应极强（χ2=15.32,P〈0.01）;与其他抗精神病药比较差异无显著性。结论阿立哌唑治疗精神分裂症阴性症状疗效显著,与其他抗精神病药差异无显著性,但差异效应因药物不同而异。     

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.     

Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study

BACKGROUND: Aripiprazole is a novel antipsychotic for the management of schizophrenia. This study investigated the efficacy, safety, and tolerability of aripiprazole in preventing relapse in adult chronic schizophrenia patients experiencing ongoing stable symptomatology. METHOD: In this 26-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center study, 310 patients with DSM-IV schizophrenia (mean Positive and Negative Syndrome Scale [PANSS] total score = 82) were randomly assigned to receive a once-daily fixed dose of aripiprazole, 15 mg, or placebo. The primary outcome measure was time to relapse following randomization. Secondary objectives were to assess the efficacy, safety, and tolerability of aripiprazole, 15 mg, compared with placebo, in the study population. The study was conducted between Dec. 21, 2000, and Aug. 20, 2001. RESULTS: The time to relapse following randomization was significantly (p < .001) longer for aripiprazole compared with placebo. More patients relapsed with placebo (N = 85; 57%) than aripiprazole (N = 50; 34%); the relative risk of relapse for the aripiprazole group was 0.59 (p < .001). Aripiprazole was significantly superior to placebo from baseline to endpoint in PANSS total, PANSS positive, PANSS-derived Brief Psychiatric Rating Scale, and Clinical Global Impressions-Severity of Illness scale (CGI-S) scores and demonstrated significantly better mean Clinical Global Impressions-Global Improvement scale scores (p < or = .01 for all comparisons except CGI-S: .01 < p < or = .05). Aripiprazole was well tolerated, with no evidence of marked sedation and no evidence of hyperprolactinemia or prolonged heart rate-corrected QT interval (QTc). Extrapyramidal symptoms were comparable in the aripiprazole and placebo groups. Modest mean weight loss at endpoint was evident in both groups. CONCLUSION: Aripiprazole, 15 mg once daily, is an effective, well-tolerated treatment for prevention of relapse in patients with chronic, stable schizophrenia.     

Are there any differences in the efficacy among second generation antipsychotics in the treatment of schizophrenia and related disorders?

BACKGROUND: The goal of this review is to summarize the results of head to head efficacy studies that compare second generation antipsychotics in the treatment of schizophrenia and related disorders. METHODS: A literature search through the Medline database and Google was conducted. Articles published up to September 2005 were included. Abstracts from conference papers and posters were not included. RESULTS: Randomized controlled trial data on possible differences in efficacy among atypical antipsychotics are limited. Moreover, the comparison is difficult, as studies differ in outcome measures. The results indicate that first-line second-generation antipsychotics (amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and zotepine) show comparable efficacy. CONCLUSION: Possible new studies should focus on long-term effects, including cost-effectiveness, quality of life, social functioning and service utilization.     

阿立哌唑与利培酮治疗精神分裂症研究

目的：评价阿立哌唑治疗精神分裂症的疗效及不良反应。方法：64例精神分裂症患者,随机分为两组,分别给予阿立哌唑与利培酮治疗8周。采用阳性与阴性症状量表（PANSS）、治疗中出现的症状量表（TESS）评定疗效及不良反应。结果：阿立哌唑组显效率为78.1%,利培酮组为75.0%。利培酮组锥体外系反应稍高于阿立哌唑组。结论：阿立哌唑与利培酮疗效相似,锥体外系反应比利培酮少,是一种有效、安全的抗精神病药物。