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This double-blind, multicenter study aimed to investigate the efficacy and safety of aripiprazole 10, 15 or 20 mg/day versus placebo. Patients requiring inpatient hospitalization for acute exacerbation of schizophrenia were randomized to once-daily aripiprazole 10, 15 or 20 mg/day or placebo for 6 weeks. The primary efficacy outcome was the mean change from baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) Total score (last observation carried forward). Patients with no improvement by Week 3 (Clinical Global Impression-Global Improvement score > or =4) could transfer to open-label aripiprazole 20mg/day. In total, 420 patients were randomized to placebo (n = 108); aripiprazole 10 mg/day (n = 106); 15 mg/day (n = 106); or 20 mg/day (n = 100). Of these, 142 patients (34%) completed 6 weeks of treatment, 131 (31%) discontinued to receive open-label aripiprazole, and 147 (35%) for other reasons. Aripiprazole 10, 15 and 20 mg/day each showed significantly greater improvements from baseline than placebo for all efficacy measures, including PANSS Total, Positive and Negative scores, and the CGI-Severity of Illness score. Significantly greater improvements in PANSS Total score versus placebo were achieved by Week 1 with 10 or 20 mg/day and Week 3 with 15 mg/day. All three doses were well tolerated. Overall, aripiprazole was not associated with clinically meaningful differences in extrapyramidal symptoms, prolactin or weight changes versus placebo. Aripiprazole 10 mg/day is effective and well tolerated for patients experiencing an acute exacerbation of schizophrenia.

Objective: To report efficacy and safety of transitioning patients receiving intramuscular (IM) formulations of aripiprazole or haloperidol to their respective oral formulations., Methods: 448 agitated patients with schizophrenia (73%) or schizoaffective disorder (27%) were randomized to receive aripiprazole IM 9.75 mg, haloperidol IM 6.5 mg, or placebo IM within 24 hours. Patients treated with aripiprazole IM or haloperidol IM who completed this 24-hour IM phase were transitioned to the respective blinded oral formulations for 4 days (aripiprazole 10-15 mg/day, n = 153; haloperidol 7.5-10 mg/day, n = 151). Patients treated with placebo IM were transitioned to oral aripiprazole (analysis not included). The primary efficacy measure was mean change in Positive and Negative Syndrome Scale-Excited Component (PEC) score from baseline of oral phase (last value from 24-hour IM phase) to endpoint (study day 5, last observation carried forward)., Results: During the oral phase, aripiprazole 15 mg and haloperidol 10 mg were both effective in maintaining responses achieved on all efficacy measures during the 24-hour IM phase. Mean improvements in PEC scores from study day 1 to 5 were -1.37 for aripiprazole and -1.40 for haloperidol (p = NS for aripiprazole versus haloperidol). Oral aripiprazole was well tolerated. Extrapyramidal symptom-related adverse events were lower for aripiprazole (1.3%) than haloperidol (8.0%). Nausea and vomiting occurred more frequently in patients receiving aripiprazole (3.9% and 2.6%, respectively) than in those receiving haloperidol (0.7% and 1.3%, respectively)., Conclusions: Acutely agitated patients with schizophrenia or schizoaffective disorder treated with aripiprazole IM or haloperidol IM demonstrated similar effective and safe transition to their respective oral formulations. Initial benefits of reduced agitation and improved clinical status during the IM phase of the study were maintained throughout the oral phase of the study with good tolerability.

Ziprasidone is a second-generation antipsychotic that received Food and Drug Administration approval in February 2001. It has a unique receptor profile that includes high-affinity antagonist activity at dopamine D2 receptors, inverse agonist activity at serotonin (5-HT)2A receptors, agonist activity at 5-HTlA receptors, and a relatively high affinity for the serotonin and norepinephrine transporters. The 5-HTIA affinity, together with the inhibitory effect on mono-amine reuptake, may underlie the hypothesized beneficial effects on comorbid affective and cognitive abnormalities in schizophrenia and schizoaffective disorder. The short-term efficacy of ziprasidone for core positive symptoms of schizophrenia appears to be comparable to other conventional and atypical antipsychotics. The short-term efficacy of ziprasidone in acute mania has been established based on two 3-week, double-blind, placebo-controlled trials.Open-label treatment for up to 52 weeks confirms the sustained efficacy and safety of ziprasidone in bipolar disorder. Maintenance studies in schizophrenia and schizoaffective disorder indicate that long-term ziprasidone therapy is effective in preventing relapse, while maintaining cognitive and psychosocial benefits. The safety database suggests that the overall cardiovascular and cerebrovascular risk associated with ziprasidone is lower than with other atypicals, with notably lower risk of drug-related increases in weight, glucose, or lipids. The data also suggest a modestly increased risk of QTc prolongation that is not dose related or linked to torsades de pointes. Switching to ziprasidone from other atypicals appears to improve both clinical symptoms and metabolic parameters, though more studies are needed to fully characterize these benefits. This monograph summarizes the efficacy, tolerability, and safety of oral ziprasidone in the treatment of schizophrenia, schizoaffective disorder, and bipolar mania.

The intramuscular (i.m.) formulation of ziprasidone offers promise as an alternative to conventional i.m. agents for the short-term management of agitated patients with psychosis. This 7-day, randomized, open-label study evaluated the tolerability of ziprasidone i.m. and haloperidol i.m. in hospitalized patients with a psychotic disorder and moderate psychopathology. Patients received three fixed doses of ziprasidone i.m. 5 mg qid (n=69), 10mg qid (currently maximum recommended daily dose in USA; n=71), 20mg qid (n=66), or flexible-dose/ flexible-schedule haloperidol i.m. up to 10 mg bid-qid (n=100) for 3 days. This was followed by oral treatment with the same medication for 4 days. Ziprasidone i.m. was associated with a notably lower burden of movement disorders than haloperidol i.m. (mean 11 mg/day). No bradycardia, sinus pauses, disinhibition, confusion, excessive sedation or respiratory depression was observed with ziprasidone. No safety issues were identified with the coadministration of lorazepam with the i.m. formulations of either agent. All three ziprasidone i.m. doses and haloperidol i.m. maintained control of symptoms and, following the transition to oral treatment, symptoms remained controlled. Ziprasidone i.m. 5,10, and 20 mg qid, given for 3 days were well tolerated. The transition from i.m. to oral ziprasidone was well tolerated with continuing maintenance of symptom control.

Side effect and health status changes were measured in 3 studies in which outpatients experiencing suboptimal efficacy or tolerability with their current antipsychotic were switched to 6 weeks of open-label ziprasidone. The studies differed only in the patient's prior antipsychotic; 1 study group was on olanzapine (n = 104), a second on risperidone (n = 58), and third on a conventional antipsychotic (n = 108). Baseline and end point health status measures included weight and height, nonfasting cholesterol, and triglyceride levels, prolactin levels, and extrapyramidal side effects. Improvements in health indices and side effects were seen among all 3 groups, but the specific benefits depended on the preswitch antipsychotic. For example, patients switched from olanzapine experienced a mean weight loss of 1.76 kg (P < 0.0001), those switched from risperidone had a lesser reduction in weight (-0.86 kg; P = 0.015), and those switched from conventionals had a nonsignificant increase (+0.27 kg; P = 0.3). Prolactin levels decreased among those switched from risperidone (P < 0.0001) or conventionals (P = 0.05), but not for patients switched from olanzapine. EPS improved among those switched from conventionals (P < 0.0001) and to a lesser extent among those switched from risperidone (P < 0.01), but not in those changed from olanzapine (NS). Thus, in these studies, switching to ziprasidone in patients with continuing symptoms or side effects on their current medication was often associated with improved health status indices, lowered prolactin levels, or less EPS, with the magnitude benefit consistent with the known side-effect profile of the preswitch antipsychotic.

Although atypical antipsychotic agents have improved the management of patients with schizophrenia, their utility has been hindered by some limitations, including significant weight gain, glucose metabolism disturbances, and increases in total and low-density lipoprotein cholesterol and triglyceride levels. In addition to its low liability for movement disorders and its favorable tolerability record in short- and long-term clinical trials, ziprasidone is associated with a favorable metabolic safety profile (in terms of its effect on plasma lipid and glucose levels) and a negligible effect on weight. The limited effect of ziprasidone on the corrected QT interval (QTc) has also been well characterized, and experience to date has not demonstrated any increased risk of clinical events attributable to QTc prolongation. This review of pharmacokinetic and clinical trials of ziprasidone versus placebo and active comparators focuses on the safety and tolerability of both the intramuscular and oral formulations.