Efficacy and tolerability of switching to ziprasidone from olanzapine, risperidone or haloperidol: an international, multicenter study.

To compare the effectiveness of a switch from haloperidol (N=99), olanzapine (N=82), or risperidone (N=104) to 12 weeks of treatment with 80-160 mg/day ziprasidone in patients with stable schizophrenia or schizoaffective disorder. Stable outpatients with persistent symptoms or troublesome side effects were switched using one of three 1-week taper/switch strategies as determined by the investigator. Efficacy was assessed using the Brief Psychiatric Rating Scale score, Clinical Global Impression, Positive and Negative Symptom Scale, Montgomery-Asberg Depression Rating Scale, and the Global Assessment of Functioning Scale, and tolerability by using standard measures of weight change, extrapyramidal symptoms, and laboratory findings. Suboptimal efficacy was the primary reason for switching. The preferred switch strategy was immediate discontinuation, and the preferred dosing regimen was 120 mg/day. Completer rates were 68, 60, and 86% in the haloperidol, risperidone, and olanzapine pre-switch groups, respectively. At week 12, a switch to ziprasidone resulted in statistically significant improvement from baseline on the Brief Psychiatric Rating Scale score, Clinical Global Impression-Improvement, Positive and Negative Symptom Scale, and Global Assessment of Functioning scales, reduction in extrapyramidal symptoms and a neutral impact on metabolic parameters. Switch from olanzapine and risperidone resulted in weight reduction and from haloperidol in some weight increase. In conclusion, oral ziprasidone of 80-160 mg/day with food was a clinically valuable treatment option for stable patients with schizophrenia or schizoaffective disorder experiencing suboptimal efficacy or poor tolerability with haloperidol, olanzapine, or risperidone.

Efficacy of ziprasidone against hostility in schizophrenia: Post hoc analysis of randomized, open-label study data.

OBJECTIVE: The objective was to determine the effects of sequential intramuscular/oral ziprasi-done on hostility. METHOD: A total of 572 inpatients diagnosed with DSM-IV schizophrenia or schizoaffective disorder were the subjects in a randomized, rater-blinded, 6-week, open-label study comparing sequential intramuscular and oral ziprasidone with haloperidol. The Brief Psychiatric Rating Scale (BPRS) was the principal outcome measure. To determine the effect of ziprasidone on hostility, post hoc analyses of scores on the hostility item from the BPRS were conducted. Introducing positive symptoms and akathisia as covariates tested specific antihostility effect. The study was conducted from October 23, 1998, to August 15, 2000. RESULTS: Ziprasidone demonstrated specific antihostility effects over time throughout the 42-day study period and statistically significant superiority to haloperidol on this measure in the first week of treatment (p = .0149 at first evaluation [day 1, 2, or 3]; p = .0358 at day 7). CONCLUSION: Ziprasidone is an effective treatment for hostility in patients with schizophrenia or schizoaffective disorder.

Ziprasidone and haloperidol in the treatment of acute exacerbation of schizophrenia and schizoaffective disorder: comparison of intramuscular and oral formulations in a 6-week, randomized, blinded-assessment study.

RATIONALE: Conventional intramuscular (IM) antipsychotics used in managing acute exacerbation of schizophrenia are associated with side effects such as acute dystonia. OBJECTIVES: To compare the efficacy and tolerability of sequential IM/oral ziprasidone with haloperidol in acute exacerbation of schizophrenia or schizoaffective disorder. METHODS: In a 6-week, multicenter, parallel-group, flexibly dosed study, patients were randomized to ziprasidone (IM up to 3 days, then oral 40-80 mg, b.i.d.) or haloperidol (IM up to 3 days, then oral 5-20 mg/day). Assessments were rater-blinded. RESULTS: At the end of IM treatment, patients receiving ziprasidone (n=427) showed significantly improved Brief Psychiatric Rating Scale Total (BPRS total) scores compared with those receiving haloperidol (n=138) [least-squares (LS) mean change -6.14 for ziprasidone versus -4.13 for haloperidol, P<0.0018]. At endpoint, there were no significant between-group differences in BPRS total scores. There was a significantly greater improvement in BPRS negative subscale scores in ziprasidone-treated patients, both at the end of IM treatment (LS mean change -1.15 for ziprasidone and -0.28 for haloperidol, P<0.0001) and at study endpoint (LS mean change -2.94 for ziprasidone and -2.24 for haloperidol, P<0.0001). Haloperidol-treated patients exhibited significantly greater increases in Extrapyramidal Symptom Rating Scale at end of IM treatment and at endpoint (P<0.0001). They also had significantly higher ratings on the Barnes Akathisia Scale (P<0.0001) and the Movement Disorder Burden Score (P<0.005), as well as higher incidences of movement disorder-related adverse events. CONCLUSIONS: Sequential IM and oral ziprasidone offers important efficacy and tolerability advantages over haloperidol in acute schizophrenia.

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia.

Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5-25 mg/day, n=75) or clozapine (100-500 mg/day, n=72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia.

Intramuscular ziprasidone: moving beyond the conventional in the treatment of acute agitation in schizophrenia.

The appropriate management of schizophrenia and schizoaffective disorder requires effective, safe antipsychotic agents for use across a continuum of treatment, from control of acute psychotic episodes to prevention of relapse. Intramuscular (IM) formulations are the method of choice for administering antipsychotics to schizophrenic patients who require emergency treatment but cannot take oral medication. Atypical antipsychotics are now widely acknowledged as the first-line choice for the management of patients with schizophrenia. However, use of these agents in acutely agitated psychotic patients has been limited by the lack of an IM formulation. Ziprasidone is the first, and currently only, atypical antipsychotic to be available in a rapid-acting IM formulation. This review focuses on studies evaluating the efficacy and tolerability of IM ziprasidone. In agitated psychotic patients, IM ziprasidone reduces agitation as early as 15 minutes after administration, with improvement sustained for > or = 4 hours. In patients with acute psychosis, with or without agitation, IM ziprasidone has been demonstrated to be superior to IM haloperidol in improving overall symptom severity. During the critical IM-to-oral transition, efficacy and tolerability are maintained with ziprasidone. IM ziprasidone represents an important advance over older, conventional IM agents in the treatment of the acutely ill patient with schizophrenia.

A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia.

BACKGROUND: An intramuscular (IM) formulation of olanzapine has been developed because there are no rapid-acting IM atypical antipsychotic drugs currently available in the United States for treating acute agitation in patients with schizophrenia. METHODS: Recently hospitalized acutely agitated patients with schizophrenia (N = 270) were randomized to receive 1 to 3 IM injections of olanzapine (2.5, 5.0, 7.5, or 10.0 mg), haloperidol (7.5 mg), or placebo within 24 hours. A dose-response relationship for IM olanzapine in the reduction of agitation was assessed by measuring the reduction in Positive and Negative Syndrome Scale Excited Component (PANSS-EC) scores 2 hours after the first injection. Safety was assessed by recording adverse events and with extrapyramidal symptom scales and electrocardiograms at 24 hours after the first injection. RESULTS: Olanzapine exhibited a dose-response relationship for reduction in agitation (F(1,179)= 14.4; P<.001). Mean PANSS-EC reductions 2 hours after the first injection of olanzapine (2.5 mg = -5.5; 5.0 mg = -8.1; 7.5 mg = -8.7; 10.0 mg = -9.4) were superior to those with placebo (-2.9; P =.01 vs olanzapine at 2.5 mg; P<.001 for each other olanzapine dose) but not with haloperidol (-7.5). A dose of 5.0, 7.5, or 10.0 mg of olanzapine caused a greater reduction in agitation than placebo 30 minutes after the first injection. There were no differences between treatment groups for hypotension, the most frequently reported adverse event, or for clinically relevant changes in the QTc interval. There was a greater incidence of treatment-emergent parkinsonism during treatment with IM haloperidol (16.7%) than with 2.5 (P =.03), 5.0 (P =.03), or 7.5 mg (P =.01) of IM olanzapine (0%) or with placebo (0%) (P =.01). CONCLUSIONS: Intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits a dose-response relationship in the rapid treatment of acute agitation in patients with schizophrenia and demonstrates a favorable safety profile.

A pilot study of intramuscular ziprasidone in the short-term treatment of patients with acute exacerbation of schizophrenia.

Ziprasidone is a novel antipsychotic which, in oral formulation, has been shown to be effective and well tolerated in the treatment of acute psychosis. This pilot study examined the efficacy and tolerability of the intramuscular (IM) formulation and the transition from IM to oral ziprasidone in patients with acute schizophrenia. The study design was an open, prospective, 5-day treatment trial of IM ziprasidone followed by oral dosing in 12 patients with acute exacerbation of schizophrenia. Various doses (2.5, 5, 10, or 20 mg) up to 60 mg/day total were administered over 3 days, followed by transition to oral ziprasidone on Days 4-5. All patients completed the study. Mean improvements between baseline and Day 3 were observed in Brief Psychiatric Rating Scale (47.8 to 28.9) and Clinical Global Impression of Severity (6.1 to 5.3), and improvements were maintained on Days 4 and 5. No extrapyramidal syndrome, acute dystonia, or serious adverse events were reported. In these patients, IM ziprasidone 20-60 mg/day reduced psychomotor agitation and other symptoms of psychosis. The transition from IM to oral ziprasidone was well tolerated. Copyright 2000 John Wiley & Sons, Ltd.