Ziprasidone and olanzapine

The same group of antipsychotic drugs have been evaluated for their effects on working memory (276,277) in a visual spatial version of the delayed non-matching to position paradigm (278,279). Haloperidol and risperidone exhibit marked inhibitory effects in low doses, whereas considerably higher doses of clozapine, olanzapine, and ziprasidone are required to produce similar effects (276). Sertindole and quetiapine are inactive at the doses tested (276). Long-term treatment reveals a continued memory impairment of memory by haloperidol, the development of tolerance to the effects of clozapine on memory, and continued lack of impairment by sertindole (277). 

Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R, Lackner E, Joukhadar C, Muller M, Kasper S. Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. Neuropsychopharmacology 2008 33(7) 1633-41. 

Stroup, T. S., Lieberman, J. A., McEvoy, J. P. et al. (2006). Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am. J. Psychiatry, 163, 611-22. 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

Ari pi prazole, olanzapine, quetiapine, risperidone, and ziprasidone are effective as monotherapy or as add-on therapy to lithium or valproate for acute mania. Prophylactic use of antipsychotics can be needed for some patients with recurrent mania or mixed states, but the risks versus benefits must be weighed in view of long-term side effects (e.g., obesity, type 2 diabetes, hyperlipidemia, hyperprolactinemia, cardiac disease, and tardive dyskinesia). 

Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone are FDA approved for the treatment of acute manic episodes in bipolar I disorder. 

Antipsychotics in a few small studies have been shown to be helpful. To date this research is limited to typical antipsychotics. Nevertheless, the excellent track record of atypical antipsychotics in treating schizophrenia and the lower burden of side effects lead us to recommend atypical antipsychotics as a first-line treatment for STPD as well. Low doses of risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole are all reasonable options. If no therapeutic effect is observed, doses should be increased. 

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. 

Drugs that can decrease carbamazepine serum levels include charcoal, cisplatin, doxorubicin, felbamate, hydantoins, rifampin, phenobarbital, primidone, theophylline. The serum levels of oral contraceptives, haloperidol, bupropion, anticoagulants, felbamate, valproic acid, felodipine, tricyclic antidepressants, acetaminophen, ziprasidone, voriconazole, topiramate, tiagabine, olanzapine, and lamotrigine can be lowered by carbamazepine. 

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. 

Although positive symptoms are usually the focus of acute intervention and are at least partially responsive to neuroleptics, cognitive, mood, and negative symptoms are generally more debilitating, are less responsive to conventional agents, and may be more responsive to novel antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine, ziprasidone). 

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... 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

Until recently, lithium carbonate was the universally preferred treatment for bipolar disorder, especially in the manic phase. With the approval of valproate, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone for this indication, a smaller percentage of bipolar patients now receive lithium. This trend is reinforced by the slow onset of action of lithium, which has often been supplemented with concurrent use of antipsychotic drugs or potent benzodiazepines in severely manic patients. The overall success rate for achieving remission from the manic phase of bipolar disorder can be as high as 80% but lower among patients who require hospitalization. A similar situation applies to maintenance treatment, which is about 60% effective overall but less in severely ill patients. These considerations have led to increased use of combined treatment in severe cases. After mania is controlled, the antipsychotic drug may be stopped and benzodiazepines and lithium continued as maintenance therapy. 

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