Ziprasidone and quetiapine

Most antipsychotics have half-fives of elimination in the range of 20 to 40 hours. After dosage stabilization, most antipsychotics (except quetiapine and ziprasidone) can be dosed once daily. It may be possible to dose SGAs less often than their plasma kinetics would suggest. 

The first atypical antipsychotic is clozapine. Several other atypical antipsychotics have been developed since clozapine was introduced. The first was risperidone, followed by olanzapine, quetiapine, and ziprasidone. 

Clozapine was the first atypical antipsychotic released in the United States. However, clozapine is associated with the risk of leukopenia and, potentially, lethal agranulocytosis. Because of these concerns, hematological monitoring during clozapine pharmacotherapy is required (Alphs and Anand, 1999). Due to these hematological risks, clozapine is indicated only for patients with treatment-resistant schizophrenia. The other atypical antipsychotics, risperidone, olanzapine, quetiapine, and ziprasidone, that are marketed in the United States can be used as first-line treatments for adults with schizophrenia. 

A wide range of disorders can benefit from antipsychotic therapy. For example, since the introduction of antipsychotics, 25% fewer hospital beds are occupied by patients with schizophrenia. In particular, the newer antipsychotics hold the promise of benefitting patients once refractory to conventional treatment. Thus, negative, cognitive, and mood symptoms may improve with use of newer agents such as clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. 

Risperidone and olanzapine are more effective than neuroleptics and safer than neuroleptics and clozapine, so they represent first-line choices. Quetiapine and ziprasidone are safer but may only be equal in efficacy to neuroleptics. The timing for clozapine is less certain with arguments put forth for earlier versus later introduction based on efficacy and safety issues, respectively. Clozapine is an important drug for the patients who have not fully remitted with first line drugs. 

Clozapine, risperidone, olanzapine, quetiapine, and ziprasidone have all been approved for the treatment of schizophrenia. Data from long-term open evaluations of clozapine demonstrate that improvement is maintained over time, even when the dose is reduced. Further, patients did not develop tolerance to its antipsychotic effect. Naturalistic reports indicate that an adequate trial for acute response in some patients may be at least 6 months. Further, a small number (8 of 14) of previously refractory patients were successfully maintained on clozapine for up to 2 years ( 215). 

A number of patients have been exposed to clozapine for several years and TD has not developed. Studies have also investigated patients with TD who were switched to clozapine for periods of 3 weeks to 6 months (461, 462, 463 and 464). Some appeared to improve, but these findings are difficult to interpret because control groups would be needed to demonstrate conclusively that clozapine does not cause TD. Theoretically, if clozapine does not cause acute EPS, then it should not cause TD. Other novel agents such as risperidone, olanzapine, quetiapine, and ziprasidone await longer term exposure to assess their propensity to induce TD. Thus, we agree with Casey, who wrote it is possible that compounds associated with a low rate of EPS may also produce less TD, but prospective studies are needed to confirm this premise (465). 

TABLE 5-27. Pharmacokinetics of risperidone, olanzapine, quetiapine, and ziprasidone... 

The second-generation drugs are aiso readiiy absorbed. Quetiapine and ziprasidone have short eiimination haif-iives (<10 hours) but the others have half-lives in the region of 20-30 hours. Active metaboiites generaiiy do not contribute significantly to the action of these drugs. 

The magnitude of these properties is far from trivial and, in feet, makes the four atypical antipsychotics risperidone, olanzapine, quetiapine, and ziprasidone easily preferable as first-line therapies for psychosis, with conventional antipsychotics and clozapine as second-line therapies. 

Barbee JG, Comad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry 2004 65(7) 975-981. 

Conventional antipsychotics improve symptoms of hyperactivity and impulsivity, but may have negative effects on learning and cognitive functioning as well as extrapyramidal side effects (e.g., dystonia and tardive dyskinesia) that limit their usefulness. The atypical antipsychotics risperidone, olanzapine, quetiapine, and ziprasidone have been used to control severe aggression in refractory cases of ADHD, particularly if conduct disorder or bipolar disorder coexists. More studies are needed to clarify their place in therapy. ... 

Controlled studies A QTc study of three doses of ilopeiidone was conducted in the presence of metabolic inhibitors of CYP2D6 and/or CYP3A4 with a comparison to quetiapine and ziprasidone [157 ]. Uoperidone BID produced mean changes in QTcF comparable with ziprasidone and quetiapine. A higher single daily dose of Uoperidone... 

Potkin SG, Preskorn S, Hochfeld M, Meng X. A thorough QTc study of 3 doses of Uoperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to quetiapine and ziprasidone. J Qin Psychopharmacol 2013 33(1) 3-10. 

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