Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC)

Am J Psychiatry. 2011 Feb;168(2):193-201. doi: 10.1176/appi.ajp.2010.08040484. Epub 2010 Nov 1.


Objective: The authors compared 1-year mortality rates associated with ziprasidone and olanzapine in real-world use.

Method: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) was an open-label, randomized, postmarketing large simple trial that enrolled patients with schizophrenia (N=18,154) in naturalistic practice in 18 countries. The primary outcome measure was nonsuicide mortality in the year after initiation of assigned treatment. Patients were randomly assigned to receive treatment with either ziprasidone or olanzapine and followed for 1 year by unblinded investigators providing usual care. A physician-administered questionnaire was used to collect baseline demographic information, medical and psychiatric history, and concomitant medication use. Follow-up information on hospitalizations and emergency department visits, patients' vital status, and current antipsychotic drug status was collected and reported by treating psychiatrists. Post hoc analyses of sudden death, a secondary endpoint, were also conducted.

Results: The incidence of nonsuicide mortality within 1 year of initiating pharmacotherapy was 0.91 for ziprasidone (N=9,077) and 0.90 for olanzapine (N=9,077). The relative risk was 1.02 (95% CI=0.76-1.39). This finding was confirmed in numerous secondary and sensitivity analyses.

Conclusions: Despite the known risk of QTc prolongation with ziprasidone treatment, the findings of this study failed to show that ziprasidone is associated with an elevated risk of nonsuicidal mortality relative to olanzapine in real-world use; the study excludes a relative risk larger than 1.39 with a high probability. However, the study was neither powered nor designed to examine the risk of rare events like torsade de pointes.

Trial registration: NCT00418171.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / therapeutic use
  • Antipsychotic Agents / toxicity*
  • Benzodiazepines / therapeutic use
  • Benzodiazepines / toxicity*
  • Cause of Death
  • Cross-Sectional Studies
  • Death, Sudden, Cardiac / epidemiology*
  • Death, Sudden, Cardiac / etiology*
  • Diabetic Ketoacidosis / chemically induced
  • Diabetic Ketoacidosis / mortality
  • Female
  • Hospitalization / statistics & numerical data
  • Humans
  • Incidence
  • Kaplan-Meier Estimate
  • Long QT Syndrome / chemically induced*
  • Long QT Syndrome / mortality*
  • Male
  • Middle Aged
  • Myocardial Infarction / chemically induced*
  • Myocardial Infarction / mortality*
  • Olanzapine
  • Piperazines / therapeutic use
  • Piperazines / toxicity*
  • Product Surveillance, Postmarketing
  • Prospective Studies
  • Risk
  • Schizophrenia / drug therapy*
  • Schizophrenia / mortality*
  • Suicide / statistics & numerical data
  • Thiazoles / therapeutic use
  • Thiazoles / toxicity*


  • Antipsychotic Agents
  • Piperazines
  • Thiazoles
  • Benzodiazepines
  • ziprasidone
  • Olanzapine

Associated data