An Exploratory Haloperidol-Controlled Dose-Finding Study of Ziprasidone in Hospitalized Patients With Schizophrenia or Schizoaffective Disorder

Abstract

Ninety patients with schizophrenia or schizoaffective disorder according to DSM-III-R criteria participated in this double-blind, exploratory, dose-ranging trial. After a single-blind washout period of 4 to 7 days, patients were randomly assigned to receive one of four fixed doses of the new antipsychotic, ziprasidone 4 (N = 19), 10 (N = 17), 40 (N = 17), or 160 (N = 20) mg/day or haloperidol 15 mg/day (N = 17) for 4 weeks. A dose-response relationship among ziprasidone groups was established for improvements in Clinical Global Impression Severity (CGI-S) score (p = 0.002) but not in Brief Psychiatric Rating Scale (BPRS) total score (p = 0.08). The intent-to-treat analysis of mean changes from baseline in the BPRS total, BPRS Psychosis core, and CGI-S scores demonstrated that ziprasidone 160 mg/day was comparable with haloperidol in reducing overall psychopathology and positive symptoms and was superior to ziprasidone 4 mg/day. Despite the small sample size and short duration of the trial, the improvement in CGI-S with both ziprasidone 160 mg/day and haloperidol 15 mg/day was statistically significantly greater than with ziprasidone 4 mg/day (p = 0.001 andp = 0.005, respectively). The percentage of patients classified as responders on both the BPRS total (> or = 30% improvement) and CGI-Improvement (score of 1 or 2) scales in the ziprasidone 160 mg/day group was similar to that in the haloperidol group and nonsignificantly greater than that in the ziprasidone 4 mg/day group. On all assessments of clinical efficacy, the improvements associated with ziprasidone 4 mg/day, 10 mg/day, and 40 mg/day were similar. Concomitant benztropine use at any time during the study was less frequent with ziprasidone 160 mg/day (15%) than with haloperidol (53%). Haloperidol was associated with a sustained hyperprolactinemia, unlike ziprasidone, where only transient elevations in prolactin that returned to normal within the dosing interval were observed. Ziprasidone was well tolerated, and the incidence of adverse events was similar in all groups. The results of this study suggest that ziprasidone 160 mg/day is as effective as haloperidol 15 mg/day in reducing overall psychopathology and positive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder but has a lower potential to induce extrapyramidal symptoms.

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

“…The incidence of extrapyramidal symptoms in the present study was much lower than that associated with conventional neuroleptic therapy in the literature (Ortiz and Gershon, 1986;Keepers et al 1983;Casey and Keepers 1988). This observation is consistent with the findings of another short-term study where ziprasidone in doses up to 160 mg/day were shown to have lower potential to induce movement disorders than haloperidol 15 mg/day (Goff et al 1998). Although there was evidence of a relationship between ziprasidone 160 mg/day and emergent EPS classified as an adverse event, this was very infrequent (7%).…”

“…In addition, only one patient discontinued with movement disorders. Collectively, the investigations of motor side effects undertaken in this study are consistent with the very low propensity for movement disorders predicted by the in vitro receptor binding profile, PET studies, and the relatively low potency for induction of catalepsy (Seeger et al 1995) and observed in other clinical trials (Goff et al 1998, Keck et al 1998.…”

“…In a 28-day clinical trial in which the majority of patients (84/90) had an acute exacerbation of schizophrenia or schizoaffective disorder, ziprasidone 160 mg/day reduced Brief Psychiatric Rating Scale (BPRS) total and core item scores and Clinical Global Impression of Severity (CGI-S) scores similarly to haloperidol 15 mg/day (Goff et al 1998). In a second 28-day clinical trial, involving 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder, ziprasidone 120 mg/day was significantly more effective than placebo in improving BPRS total, BPRS anxiety-depression cluster, BPRS anergia factor scores, and CGI-S (Keck et al 1998).…”

A systematic review of atypical antipsychotic drugs in schizophrenia

“…Seven RCTs were included in the original review: Arato 1997, 289 Brook 1998, 288 Daniel 1999, 290 Goff 1998, 291 Hirsch 1999, 292 , 293 Swift 1998. 294 Data extraction sheets for these studies can be found in appendix 3.…”

Occupancy of Agonist Drugs at the 5-HT1A Receptor

“…In human PET studies, 40 mg oral ziprasidone occupies B72% D 2 receptors using the D 2 antagonist radiotracer [ 11 C]raclopride (Bench et al, 1996) and B95% 5-HT 2A receptors using the 5-HT 2A antagonist radioligand [ 18 F]setoperone (Fischman et al, 1996) 4-8 h post-dose. In patients with acute exacerbations of schizophrenia and schizoaffective disorder, randomized double-blind studies have shown ziprasidone to have efficacy superior to placebo (Daniel et al, 1999;Keck et al, 1998) and similar to haloperidol (Goff et al, 1998). In stable patients, it reduces relapse rate compared to placebo (Arato et al, 2002) and appears to have higher efficacy against negative symptoms than haloperidol (Hirsch et al, 2002).…”