High-Dose Oral Ziprasidone Versus Conventional Dosing in Schizophrenia Patients With Residual Symptoms

Ziprasidone is an atypical antipsychotic medication which has demonstrated efficacy
comparable to or superior to conventional antipsychotics at doses ranging from 80 to 160
mg/d and is relatively free of weight-gain, extrapyramidal side effects, and prolactin
elevation. Early dose finding trials predicted that a dose of 20-40 mg/d would produce
optimal striatal D2 occupancy with repeated dosing. This estimate was later found to be
incorrect, as clinical efficacy was not observed at doses below 80mg/d. Doses greater than
160mg/d were not systematically studied in randomized dose finding trials. The range of
ziprasidone doses studies in early dose finding trials was constrained by concerns about
cardiac conduction effects at higher doses. It has subsequently been shown that QTc
prolongation is minimally increased with elevations in ziprasidone blood levels above those
typically achieved with a dose of 160mg/day. In addition, ziprasidone 320mg/day did not
produce significant QTc delay compared to ziprasidone 160mg/day in a randomized, prospective
safety study. Deutchman and Deutchman described their clinical experience with high-dose
ziprasidone stating that half of the patients experienced significant improvement in
psychosis and affective symptoms following dose escalation. The investigators reported the
high-dose ziprasidone was generally well-tolerated, with 75% reporting no side-effects and
fewer than 10% reporting sedation, which was the most common complaint. One patient dropped
out due to restlessness. Given that some patients may require ziprasidone doses above
160mg/day to achieve optimal D2 occupancy, the good tolerability, the absence of significant
cardiac conduction effects at higher doses, and positive findings in a preliminary trial of
high-dose ziprasidone, we propose to conduct a randomized, 8-week, placebo-controlled trial
of dose escalation in patients who remain symptomatic after at least 3 weeks treatment with
ziprasidone 160mg/day.

The study will include adult inpatients or outpatients with Schizophrenia or schizoaffective
disorder who remain symptomatic despite treatment with ziprasidone 160mg/d for at least 3
weeks. The study will encourage a prospective, open-label trial of ziprasidone lasting at
least 3 weeks for most subjects in order to verify treatment resistance; written informed
consent is required for these subjects at the start of the open treatment period. Study-wide
we expect to enroll 80 total subjects. At the MGH site we expect to enroll 8 subjects.

The proposed trial will be placebo-controlled, randomized, and double-blind. Subjects who
are treatment resistant and meet entry criteria will then be randomly allocated to receive
ziprasidone or placebo added-on to their open-label dose of ziprasidone for 8 weeks.
Subjects will be stratified within each arm according to the duration of prior ziprasidone
treatment (less than 6 weeks or 6 weeks and longer; for purposes of stratification this will
be described as "brief" or "chronic" treatment respectively). All subjects will be randomly
assigned to ziprasidone 40 mg capsules or matching placebo in a 1:1 ratio, stratified
according to duration of prior ziprasidone treatment. Subjects will be instructed to take
one study capsule twice daily (total of 80 mg/d) added to their regular open-label
ziprasidone dose (total of 240 mg/d). After the first week, the study drug will be
increased to two tablets twice daily (160 mg/d) for a total of 320 mg/d. Subjects assigned
to placebo will remain on open-label ziprasidone 160 mg/d during the study.

Overall there are 7 study visits. On each visit, subjects will be evaluated with standard
psychiatric rating scales of psychopathology, cognition, and side effects. In addition, we
will measure serum levels of the medications used, fasting blood labs, drug screens, a
pregnancy test, vital signs, and EKGs at multiple points during the study.

SCoRS Informants will complete the SCoRS rating scale at two time points: Baseline and Week
8.

The two primary endpoints will be the mean improvement in PANSS total score from baseline
and response rate defined as a reduction in the PANSS total score from baseline by 20% or
greater. Secondary endpoints will include mean improvements in the PANSS Positive and
Negative Syndrome subscales, mean improvement in the Calgary Depression Rating Scale total
score and change in GAF, CGI, and SCoRS scores. Tolerability will be measured by completion
rates, changes in vital signs, treatment-emergent side effects, the SAS, BAS, and AIMS total
scores, frequency of abnormal laboratory measures, and an increase in the QTc to 500 msec or
greater.