Ziprasidone for psychotic disorders: a meta-analysis and systematic review of the relationship between pharmacokinetics, pharmacodynamics, and clinical profile.

Abstract

BACKGROUND:

Among atypical antipsychotics, ziprasidone exhibits a unique clinical profile. However, prescription rates for this medication remain among the lowest of all atypical antipsychotics.

OBJECTIVE:

The present meta-analysis examined premature study discontinuation (PSD) and dose-response associated with ziprasidone. Furthermore, a systematic review of the clinical pharmacokinetic and pharmacodynamic properties and tolerability of ziprasidone was conducted to explain the meta-analytic findings.

METHODS:

A systematic search was performed in the electronic databases PubMed and EMBASE using the key words ziprasidone, randomized, positron emission tomography, pharmacokinetic, and tolerability. This search looked for open-label or blinded studies of oral ziprasidone use in patients with psychoses (schizophrenia-spectrum disorders and/or bipolar mania) published between January 1, 1992, and February 1, 2011. Comparisons with antipsychotics for which there were <3 studies in total were excluded. PSD (all causes) was used as a measure of overall effectiveness.

RESULTS:

Thirty-one studies were included in the final analysis. The rates of PSD were significantly higher with ziprasidone compared with olanzapine (inefficacy and all causes, P < 0.001) and risperidone (all causes, P = 0.004). In contrast, the rates of PSD due to inefficacy and adverse events were significantly lower with ziprasidone compared with quetiapine (P = 0.03) and haloperidol (P = 0.03), respectively. On dose-response analysis, the rate of all-cause PSD was significantly lower with combined 120-160 mg/d compared with placebo (P = 0.001). Low levels of hyperprolactinemia and weight gain/metabolic adverse events, and moderate extrapyramidal symptoms and corrected QT-interval prolongation were reported with ziprasidone use. Ziprasidone exposure was increased when the medication was administered with food, irrespective of fat content. Ziprasidone 120-160 mg/d was correlated with 60% to 80% occupancy in studies of D(2) binding with the administration of multiple doses. However, the same occupancy was achieved with single-dose administration at much lower doses (20-60 mg/d).

CONCLUSIONS:

The findings from this meta-analysis and review suggest that ziprasidone 120-160 mg/d is a less effective treatment for psychotic disorders compared with olanzapine and risperidone, but that the low levels of hyperprolactinemia and weight gain/metabolic adverse events associated with ziprasidone may make it a useful option in patients in whom antipsychotics are poorly tolerated for these reasons.

• Authors: Emmanuel Stip, Simon Zhornitsky, Hoda Moteshafi, Geneviève Létourneau, Irena Stikarovska, Stéphane Potvin, Valérie Tourjman
• Journal: Clinical therapeutics (Clin Ther) Vol. 33 Issue 12 Pg. 1853-67 (Dec 2011) ISSN: 1879-114X [Electronic] United States
• PMID: 22133697 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't, Review, Systematic Review)
• Copyright: Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Chemical References

• Antipsychotic Agents
• Dopamine Antagonists
• Dopamine D2 Receptor Antagonists
• Piperazines
• Receptors, Dopamine D2
• Thiazoles
• ziprasidone

Topics

• Antipsychotic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Dopamine Antagonists (administration & dosage, adverse effects, pharmacokinetics)
• Dopamine D2 Receptor Antagonists
• Dose-Response Relationship, Drug
• Evidence-Based Medicine
• Food-Drug Interactions
• Humans
• Patient Selection
• Piperazines (administration & dosage, adverse effects, pharmacokinetics)
• Psychotic Disorders (diagnosis, drug therapy, metabolism, psychology)
• Receptors, Dopamine D2 (metabolism)
• Risk Assessment
• Thiazoles (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome