Schizophrenia
The efficacy of oral ziprasidone in the treatment of schizophrenia was evaluated in 5
placebo-controlled studies, 4 short-term (4- and 6-week) trials and one maintenance
trial. All trials were in adult inpatients, most of whom met DSM III-R criteria for
schizophrenia. Each study included 2 to 3 fixed doses of ziprasidone as well as placebo.
Four of the 5 trials were able to distinguish ziprasidone from placebo; one short-term
study did not. Although a single fixed-dose haloperidol arm was included as a comparative
treatment in one of the three short-term trials, this single study was inadequate to provide
a reliable and valid comparison of ziprasidone and haloperidol.
Several instruments were used for assessing psychiatric signs and symptoms in these
studies. The Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative
Syndrome Scale (PANSS) are both multi-item inventories of general psychopathology
usually used to evaluate the effects of drug treatment in schizophrenia. The BPRS
psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness,
and unusual thought content) is considered a particularly useful subset for assessing
actively psychotic schizophrenic patients. A second widely used assessment, the
Clinical Global Impression (CGI), reflects the impression of a skilled observer,
fully familiar with the manifestations of schizophrenia, about the overall clinical
state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS)
was employed for assessing negative symptoms in one trial.
The results of the oral ziprasidone trials in schizophrenia follow:
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In a 4-week, placebo-controlled trial (n=139) comparing 2 fixed doses of ziprasidone
(20 and 60 mg twice daily) with placebo, only the 60 mg dose was superior to placebo
on the BPRS total score and the CGI severity score. This higher dose group was not
superior to placebo on the BPRS psychosis cluster or on the SANS.
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In a 6-week, placebo-controlled trial (n=302) comparing 2 fixed doses of ziprasidone
(40 and 80 mg twice daily) with placebo, both dose groups were superior to placebo on
the BPRS total score, the BPRS psychosis cluster, the CGI severity score and the PANSS
total and negative subscale scores. Although 80 mg twice daily had a numerically greater
effect than 40 mg twice daily, the difference was not statistically significant.
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In a 6-week, placebo-controlled trial (n=419) comparing 3 fixed doses of ziprasidone
(20, 60, and 100 mg twice daily) with placebo, all three dose groups were superior to
placebo on the PANSS total score, the BPRS total score, the BPRS psychosis cluster, and
the CGI severity score. Only the 100 mg twice daily dose group was superior to placebo
on the PANSS negative subscale score. There was no clear evidence for a dose-response
relationship within the 20 mg twice daily to 100 mg twice daily dose range.
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In a 4-week, placebo-controlled trial (n=200) comparing 3 fixed doses of ziprasidone
(5, 20, and 40 mg twice daily), none of the dose groups was statistically superior to
placebo on any outcome of interest.
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A study was conducted in stable chronic or subchronic (CGI-S <5 at baseline) schizophrenic
inpatients (n=294) who had been hospitalized for not less than two months. After a 3-day single-blind
placebo run-in, subjects were randomized to one of 3 fixed doses of ziprasidone (20 mg, 40 mg, or 80 mg
twice daily) or placebo and observed for relapse. Patients were observed for “impending psychotic relapse,”
defined as CGI-improvement score of ≥6 (much worse or very much worse) and/or scores ≥6 (moderately severe)
on the hostility or uncooperativeness items of the PANSS on two consecutive days. Ziprasidone was significantly
superior to placebo in time to relapse, with no significant difference between the different dose groups.
There were insufficient data to examine population subsets based on age and race. Examination of population
subsets based on gender did not reveal any differential responsiveness.
Bipolar I Disorder
Acute Manic and Mixed Episodes Associated with Bipolar I Disorder
The efficacy of ziprasidone was established in 2 placebo-controlled, double-blind, 3-week monotherapy studies in
patients meeting DSM-IV criteria for bipolar I disorder, manic or mixed episode with or without psychotic features.
Primary rating instruments used for assessing manic symptoms in these trials were: (1) the Mania Rating Scale (MRS),
which is derived from the Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-CB) with items
grouped as the Manic Syndrome subscale (elevated mood, less need for sleep, excessive energy, excessive activity,
grandiosity), the Behavior and Ideation subscale (irritability, motor hyperactivity, accelerated speech, racing
thoughts, poor judgment) and impaired insight; and (2) the Clinical Global Impression-Severity of Illness Scale
(CGI-S), which was used to assess the clinical significance of treatment response.
The results of the oral ziprasidone trials in adult bipolar I disorder, manic/mixed episode follow: in a 3-week
placebo-controlled trial (n=210), the dose of ziprasidone was 40 mg twice daily on Day 1 and 80 mg twice daily
on Day 2. Titration within the range of 40-80 mg twice daily (in 20 mg twice daily increments) was permitted for
the duration of the study. Ziprasidone was significantly more effective than placebo in reduction of the MRS total
score and the CGI-S score. The mean daily dose of ziprasidone in this study was 132 mg. In a second 3-week
placebo-controlled trial (n=205), the dose of ziprasidone was 40 mg twice daily on Day 1. Titration within the
range of 40-80 mg twice daily (in 20 mg twice daily increments) was permitted for the duration of study (beginning on Day 2). Ziprasidone was significantly more effective than placebo in reduction of the MRS total score and the CGI-S score. The mean daily dose of ziprasidone in this study was 112 mg.
Maintenance Therapy
The efficacy of ziprasidone as adjunctive therapy to lithium or valproate in the maintenance treatment of bipolar
I disorder was established in a placebo-controlled trial in patients who met DSM-IV criteria for bipolar I disorder.
The trial included patients whose most recent episode was manic or mixed, with or without psychotic features. In the
open-label phase, patients were required to be stabilized on ziprasidone plus lithium or valproic acid for at least 8
weeks in order to be randomized. In the double-blind randomized phase, patients continued treatment with lithium or
valproic acid and were randomized to receive either ziprasidone (administered twice daily totaling 80 mg to 160 mg per day)
or placebo. Generally, in the maintenance phase, patients continued on the same dose on which they were stabilized during
the stabilization phase. The primary endpoint in this study was time to recurrence of a mood episode (manic, mixed or
depressed episode) requiring intervention, which was defined as any of the following: discontinuation due to a mood
episode, clinical intervention for a mood episode (e.g., initiation of medication or hospitalization), or Mania Rating
Scale score ≥18 or a MADRS score ≥18 (on 2 consecutive assessments no more than 10 days apart). A total of 584 subjects
were treated in the open-label stabilization period. In the double-blind randomization period, 127 subjects were treated
with ziprasidone, and 112 subjects were treated with placebo. Ziprasidone was superior to placebo in increasing the time
to recurrence of a mood episode. The types of relapse events observed included depressive, manic, and mixed episodes.
Depressive, manic, and mixed episodes accounted for 53%, 34%, and 13%, respectively, of the total number of relapse
events in the study.
Acute Agitation in Schizophrenic Patients
The efficacy of intramuscular ziprasidone in the management of agitated schizophrenic
patients was established in two short-term, double-blind trials of schizophrenic
subjects who were considered by the investigators to be “acutely agitated” and in
need of IM antipsychotic medication. In addition, patients were required to have
a score of 3 or more on at least 3 of the following items of the PANSS:
anxiety, tension, hostility and excitement. Efficacy was evaluated by analysis of
the area under the curve (AUC) of the Behavioural Activity Rating Scale (BARS) and
Clinical Global Impression (CGI) severity rating. The BARS is a seven point scale
with scores ranging from 1 (difficult or unable to rouse) to 7 (violent, requires
restraint). Patients' scores on the BARS at baseline were mostly 5 (signs of overt
activity [physical or verbal], calms down with instructions) and as determined by
investigators, exhibited a degree of agitation that warranted intramuscular therapy.
There were few patients with a rating higher than 5 on the BARS, as the most severely
agitated patients were generally unable to provide informed consent for participation
in premarketing clinical trials.
Both studies compared higher doses of ziprasidone intramuscular with a 2 mg control
dose. In one study, the higher dose was 20 mg, which could be given up to 4 times
in the 24 hours of the study, at interdose intervals of no less than 4 hours.
In the other study, the higher dose was 10 mg, which could be given up to 4 times
in the 24 hours of the study, at interdose intervals of no less than 2 hours.
The results of the intramuscular ziprasidone trials follow:
(1) In a one-day, double-blind, randomized trial (n=79) involving doses of ziprasidone
intramuscular of 20 mg or 2 mg, up to QID, ziprasidone intramuscular 20 mg was statistically
superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0
to 4 hours, and by CGI severity at 4 hours and study endpoint.
(2) In another one-day, double-blind, randomized trial (n=117) involving doses of
ziprasidone intramuscular of 10 mg or 2 mg, up to QID, ziprasidone intramuscular
10 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed
by AUC of the BARS at 0 to two hours, but not by CGI severity.