title: 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: Department of Psychiatry, University of Montréal, Montréal, Québec, Canada. emmanuel.stip@umontreal.ca
authors: Emmanuel
authors: E
authors: Stip
authors: Simon
authors: S
authors: Zhornitsky
authors: Hoda
authors: H
authors: Moteshafi
authors: Geneviève
authors: G
authors: Létourneau
authors: Irena
authors: I
authors: Stikarovska
authors: Stéphane
authors: S
authors: Potvin
authors: Valérie
authors: V
authors: Tourjman
mesh_terms: D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D019317:Evidence-Based Medicine; D018565:Food-Drug Interactions; D006801:Humans; D018579:Patient Selection; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011618:Psychotic Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D018570:Risk Assessment; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D017448:Receptors, Dopamine D2; D013844:Thiazoles; C092292:ziprasidone