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

The primary aims of this study are to assess tolerability of ziprasidone dose escalation to 320 milligrams per day (mg/d) compared to continued standard treatment (placebo) as measured by the Side Effect Checklist, Simpson Angus Scale for Extrapyramidal Symptoms (SAS), Barnes Akathisia Scale (BAS), serum prolactin concentrations, vital signs, electrocardiogram (EKG) and completion rates and to assess whether ziprasidone dose escalation improves overall psychopathology compared to continued standard treatment as measured by the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score and response rates as defined by a 20% or greater reduction in PANSS total score.

The secondary aims of this study are to assess whether ziprasidone dose escalation improves psychotic symptoms compared to continued standard treatment as measured by the Positive Symptom Subscale of the PANSS, to assess whether ziprasidone dose escalation improves negative symptoms compared to standard treatment as measured by the Negative Symptom Subscale of the PANSS, to assess whether ziprasidone dose escalation improves depressive symptoms compared to continued standard treatment as measured by the Calgary Depression Rating Scale (CDRS), and to assess whether ziprasidone dose escalation improves overall functioning with the Clinical Global Impression - Severity (CGI-S), Clinical Global Impression - Improvement (CGI-I), Global Assessment of Functioning (GAF) and the Schizophrenia Cognition Rating Scale (SCoRS).

• Drug: Ziprasidone 80-160 mg/d
  Participants will be instructed to take one study capsule of ziprasidone orally twice daily (80 mg/d). After the first week, the study drug will be increased to two capsules twice daily (160 mg/d).
  Other Name: Geodon
• Drug: Placebo
  Participants will be instructed to take one study capsule of matching placebo orally twice daily. After the first week, the matching placebo will be increased to two capsules twice daily.
• Drug: Ziprasidone 160 mg/d
  Participants will be taking open-label ziprasidone 80 mg orally twice daily for a total dose of 160 mg/d from at least 3 weeks before randomization to end of study 8 weeks after randomization.
  Other Name: Geodon

• Experimental: High-Dose Ziprasidone
  Participants with schizophrenia or schizoaffective disorder who remain symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks will be instructed to take ziprasidone oral capsule twice daily added to their regular open-label ziprasidone dose (total of 240 mg/d). After the first week, the study drug will be increased to a total ziprasidone dose of 320 mg/d for 7 weeks.
  Interventions:

  • Drug: Ziprasidone 80-160 mg/d
  • Drug: Ziprasidone 160 mg/d
• Placebo Comparator: Placebo, Standard Treatment Ziprasidone
  Participants with schizophrenia or schizoaffective disorder who remain symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks will be instructed to take matching placebo oral capsule twice daily added to their regular open-label ziprasidone dose of 160 mg/d. After the first week, the matching placebo will be increased to two capsules twice daily and their regular open-label ziprasidone will remain the same (160 mg/d) for 7 weeks.
  Interventions:

  • Drug: Placebo
  • Drug: Ziprasidone 160 mg/d

Inclusion Criteria:

• Schizophrenia or Schizoaffective disorder, any subtype
• Age 18-65 years
• Treated with ziprasidone at a dose of 160 mg/d for at least 3 weeks with adequate compliance
• Concomitant standing or other medications as needed (except other antipsychotics and those noted as contraindicated in the ziprasidone package insert) are permitted during all treatment phases if they were present at a stable dose for at least 6 weeks prior to the start of initial ziprasidone treatment
• A score of 4 (moderate) or greater on any of the 7 items of the PANSS Positive Symptom Subscale
• Clinical judgment by the investigator that doses higher than 160 mg/day are warranted due to suboptimal clinical outcome despite adequate treatment at that dose
• Participant is judged capable of understanding all relevant risks and potential benefits of the study and has signed informed consent
• Comorbid axis 1 conditions (including anxiety disorders, eating disorders, impulse control disorders) are permitted if they have been stable and have not been a primary focus of treatment over the previous 6 months

Exclusion Criteria:

• Past or current intolerance of ziprasidone side effects
• Presence of significant cardiac disease, including uncompensated congestive heart failure, myocardial infarction within the past 6 months or known history of congenital long QT interval syndrome
• Corrected QT interval (QTc) greater than or equal to 500 milliseconds (msec)
• Serum potassium and magnesium concentrations outside of normal limits.
• Currently taking any medications which may affect cardiac conduction
• Presence of any unstable or untreated medical disorder
• Any history of seizures or seizure disorder other than febrile seizures of childhood
• History of positive hepatitis B surface antigen
• Human immunodeficiency virus (HIV) positive or has diagnosis of acquired immune deficiency syndrome (AIDS)
• Any abnormal laboratory test that is judged to be clinically significant by the investigator
• History of neuroleptic malignant syndrome (NMS), hypersensitivity or allergic response to antipsychotic therapy, including ziprasidone
• History of clozapine treatment for refractory psychotic symptoms
• Alcohol or substance dependence within the past 12 months or abuse within the past 3 months. Any subject with positive urine toxicology or alcohol use that is considered abnormal at baseline.
• Clinically significant suicidal or homicidal behavior or attempts within past 6 months
• Any subject judged by the investigator to present a danger to self or others.
• Women of childbearing potential who are not using adequate contraception (oral contraceptives, barrier methods or who are clearly abstinent)
• Pregnancy or breast-feeding
• Any subject who is judged by the investigator to be unable or unlikely to comply with all study requirements, including adherence with prescribed medication regimen