The development of new atypical antipsychotics and their introduction to the U.S. market has been proceeding at a fast pace. The Table provides an overview of their indications, formulations available, dosing, efficacy and safety in typical adult patients. More detailed information on dosing, as well as on treatment-resistant schizophrenia, can be found elsewhere (Citrome et al., 2002; Citrome and Volavka, 2002). The most recent additions to the antipsychotic armamentarium, ziprasidone (Geodon) and aripiprazole (Abilify), differ from the previously available products in their mechanisms of action and side-effect profiles. Antipsychotic efficacy of these two agents appears similar to older agents, but definitive head-to-head, randomized clinical trials will be required to answer questions about relative efficacy. Also reviewed is information about a new intramuscular (IM) formulation of olanzapine (Zyprexa) and an indication for clozapine (Clozaril) recently approved by the U.S. Food and Drug Administration.
Ziprasidone acts as a D2, 5-HT2A, 5-HT1D and H1 antagonist, and as a 5-HT1A agonist. This combination of activities, somewhat different from those of other antipsychotics, may be responsible for ziprasidone's pattern of side effects. Unlike most other antipsychotics, it does not have significant effects on weight, lipid profile or glucose metabolism. Furthermore, it shows low rate of persistent prolactin elevation and low incidence of extrapyramidal symptoms (EPS). Ziprasidone increases the QTC, however, and this particular side effect has raised concerns about its cardiac safety. Such prolongation increases the risk of torsade de pointes, a ventricular tachycardia-fibrillation with a characteristic electrocardiogram (ECG) presentation. Episodes of torsade de pointes may be brief and self-limiting. They may also be manifested by syncope. Torsade de pointes rarely progresses to typical ventricular fibrillation and death. This risk must be evaluated in the context of the fact that no cases of mortality from ziprasidone overdoses or torsade de pointes and no excess in sudden and unexpected deaths have so far been reported, even though by mid-2002 more than 150,000 patients received long-term treatment (Glassman and Bigger, 2002), and an overdose of 4020 mg of ziprasidone elicited only minor ECG changes (House, 2002).
Nevertheless, ziprasidone should not be co-administered with other agents--mostly antifungal and antibacterial drugs listed in the Physicians' Desk Reference--that are known to prolong the QT interval. Furthermore, it should not be prescribed for patients with an overt cardiovascular disease or a history of cardiac arrhythmias. Electrocardiogram monitoring at baseline and then at regular intervals during ziprasidone treatment has been recommended by a group of experts (Marder et al., 2002), but the value of such monitoring has not been demonstrated. Perhaps the baseline ECG should be limited to patients over 55 years of age (Glassman and Bigger, 2002). Congenital prolongation of the QT interval is one of the circumstances that raise the risk of torsade de pointes; this condition may not be apparent without a baseline ECG. Actual cardiac risk of ziprasidone treatment remains to be assessed by long-term surveillance of a large number of treated cases, but the evidence available so far does not suggest that this is going to be a major problem. The risk of cardiac arrhythmia with ziprasidone (which may turn out to be small) must be weighed against the more established risks that have been associated with some other atypical antipsychotics (agranulocytosis, weight gain, glucose and lipid metabolism, and prolactin elevation, among others).
The antipsychotic efficacy of ziprasidone is presumably mediated by the combination of D2 and 5-HT2A antagonism. In double-blind studies of oral medication lasting four to six weeks, ziprasidone (80 mg/day to 160 mg/day) was generally superior to placebo in the treatment of schizophrenia or schizoaffective disorder (Daniel et al., 1999; Keck et al., 1998). Data from a four-week trial indicated that ziprasidone 160 mg/day has similar efficacy to haloperidol (Haldol) 15 mg/day (Goff et al., 1998). The availability of a short-acting IM formulation for acute psychosis with agitation is a major advantage of ziprasidone (Citrome, 2002). After an IM dose of 10 mg, peak plasma concentrations are reached within 30 minutes to 45 minutes, with concurrent clinically significant calming effect (FDA Psychopharmacological Drugs Advisory Committee, 2001b). Ziprasidone IM reduced agitated behavior more rapidly and with fewer EPS than IM haloperidol. Starting treatment of an acute schizophrenic episode with IM injections of an atypical antipsychotic like ziprasidone offers the possibility of a seamless transition to oral treatment with the same drug, obviating the necessity of switching from IM haloperidol to a generally more preferable atypical antipsychotic.
A short-acting IM formulation of olanzapine is expected to be launched in the United States in 2003 (Citrome, 2002). Peak plasma concentration after an IM injection is reached within 15 minutes to 30 minutes. In treating acute agitation in schizophrenia, 10 mg olanzapine IM was more effective than 7.5 mg haloperidol IM (and than IM placebo) at 15 minutes after the initial injection, and this advantage was sustained during the first hour after the injection (Wright et al., 2001). Similar results were reported in agitated patients with mania and with dementia (FDA Psychopharmacological Drugs Advisory Committee, 2001a).
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