Edmund Patrick Harrigan

Ziprasidone 80 mg/day and 160 mg/day in the Acute Exacerbation of Schizophrenia and Schizoaffective Disorder: A 6-Week Placebo-Controlled Trial

In this double-blind study, patients with an acute exacerbation of schizophrenia or schizoaffective disorder were randomized to receive either ziprasidone 80 mg/day (n = 106) or 160 mg/day (n = 104) or placebo (n = 92), for 6 weeks. Both doses of ziprasidone were statistically significantly more effective than placebo in improving the PANSS total, BPRS total, BPRS core items, CGI-S, and PANSS negative subscale scores (p < .05). Ziprasidone 160 mg/day significantly improved depressive symptoms in patients with clinically significant depression at baseline (MADRS ≥ 14, over-all mean 23.5) (p < .05) as compared with placebo. The percentage of patients experiencing adverse events was similar in each treatment group, and resultant discontinuation was rare. The most frequent adverse events associated with ziprasidone were generally mild dyspepsia, nausea, dizziness, and transient somnolence. Ziprasidone was shown to have a very low liability for inducing movement disorders and weight gain. The results indicate that ziprasidone is effective and well tolerated in the treatment of the positive, negative, and depressive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder.

A Randomized Evaluation of the Effects of Six Antipsychotic Agents on Qtc, In the Absence and Presence of Metabolic Inhibition

Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.

Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder : a 4-week placebo-controlled trial

Abstract A double-blind, placebo-controlled, multicenter study, was performed to evaluate the efficacy and safety of ziprasidone in 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder. Patients were randomized to receive ziprasidone 40 mg/day, 120 mg/day or placebo for 28 days. Ziprasidone 120 mg/day was significantly more effective than placebo in improving the BPRS total, CGI-S, BPRS depression cluster and BPRS anergia cluster scores (all P < 0.05). Similarly, the percentages of patients classified as responders on the BPRS (≥30% reduction) and the CGI improvement (score ≤2) were significantly greater with ziprasidone 120 mg/day compared with placebo (P < 0.05). The number of patients who experienced an adverse event was similar in all three treatment groups, and discontinuation due to adverse events was rare (five of 91 ziprasidone-treated patients). The most frequently reported adverse events, that were more common in either ziprasidone group than in the placebo group, were dyspepsia, constipation, nausea and abdominal pain. There was a notably low incidence extrapyramidal side-effects (including akathisia) and postural hypotension and no pattern of laboratory abnormalities or apparent weight gain. Ziprasidone-treated patients were not clinically different from placebo-treated patients on the Simpson-Angus Rating scale, Barnes Akathisia scale and AIMS assessments. These results indicate that ziprasidone 120 mg/day is effective in the treatment of the positive, negative and affective symptoms of schizophrenia and schizoaffective disorder with a very low side-effect burden.

Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double- blind, placebo-controlled, multicenter studies.

This study assessed the efficacy of ziprasidone for the treatment of schizoaffective disorder. Data were taken from subsets of patients with schizoaffective disorder, derived from two separate double-blind, placebo-controlled, parallel-group, multicenter studies. A total of 115 hospitalized patients with an acute episode of schizoaffective disorder were randomly assigned to receive either fixed oral doses of ziprasidone 40 mg/day (N = 16), 80 mg/day (N = 18), 120 mg/day (N = 22), 160 mg/day (N = 25), or placebo (N = 34) for 4 to 6 weeks. Mean baseline-to-endpoint changes in Brief Psychiatric Rating Scale (BPRS) total, BPRS Core, Clinical Global Impressions Severity scale (CGI-S), BPRS Depressive, BPRS Manic, and Montgomery-Åsberg Depression Rating Scale total scores were compared between the placebo and ziprasidone groups. Neurological (Simpson-Angus, Barnes Akathisia, Abnormal Involuntary Movement Scale [AIMS]) and other side effects were also assessed. Significant dose-related improvements on all primary efficacy variables (BPRS total, BPRS Core, CGI-S) and for BPRS Manic items were observed with ziprasidone treatment in a combined analysis of data from both studies (p ≤ 0.01). Ziprasidone 160 mg/day was significantly more effective than placebo in improving mean BPRS total, BPRS Core, BPRS Manic, and CGI-S scores (p < 0.05). At 120 mg/day, ziprasidone was significantly more effective than placebo in improving mean CGI-S scores (p < 0.05). The incidence of individual adverse events was generally low in all treatment groups and was not dose-related. In addition, no significant differences were observed between baseline-to-endpoint mean changes in Simpson-Angus and AIMS scores with placebo or ziprasidone 40 to 160 mg/day. These results suggest that ziprasidone may have efficacy in the treatment of affective as well as psychotic symptoms of schizoaffective disorder, with a low side-effect burden.

The tolerability of intramuscular ziprasidone and haloperidol treatment and the transition to oral therapy.

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), 10 mg qid (currently maximum recommended daily dose in USA; n=71), 20 mg 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.

576 – The efficacy and safety of ziprasidone 80 mg/day and 160mg/day in schizophrenia and schizoaffecfive disorder

Ziprasidones high affinity for SHT1A and moderate affinity for D1 receptors suggest significant antipsychotic efficacy with low extrapyramidal side-effect (EPS) liability. This 6-week, double-blind, placebo-controlled study compared the efficacy and safety ofziprasidone in patients with an acute exacerbation of schizophrenia or schizoaffective disorder. After a 3-7 day washout, patients received either ziprasidone 40 mg bid (n= 106); ziprasidone 40 mg bid on days 1-2 then 80 mg bid (n= 104); or placebo (n=92). Both 80 mg and 160 mg/day ziprasidone significantly improved Brief Psychiatric Rating Scale (BPRSd) derived from the Positive and Negative Syndrome Scale (PANSS), BPRSd Core Items, Clinical Global Impression (CGI) Severity, and PANSS Total scores compared with placebo. Improvements in negative symptoms (PANSS Negative Subscale) were significantly greater and improvements in MADRS also greater with both ziprasidone doses compared with placebo. Notable was the low incidence of EPS, akathisia and sexual dysfunction associated with ziprasidone. Discontinuations due to adverse events were infrequent and similar among groups (4.7-9.6%). The results of this study indicate that ziprasidone is an effective and well tolerated antipsychotic, improving positive, negative and affective symptoms without an undue side-effect burden. • The authors thank the Ziprasidone Study Group for participation in this study.