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Increasing variations in mechanisms of action of atypical antipsychotics, side-effect profiles, and efficacy among the atypicals enable clinicians to tailor treatments to individual response, side-effect history, and current medical conditions.
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).
Aripiprazole acts as a partial D2 and 5-HT1A agonist. Presumably, it acts like a D2 antagonist when dopaminergic activity (which may be causing psychotic symptoms) is increased, and as an agonist when the activity is decreased. Thus, instead of simply blocking the D2 receptor like other antipsychotics, it acts like a dopamine system stabilizer. This novel mechanism of action, different from other antipsychotics, may account for its different side-effect profile: it causes essentially no EPS, no elevation of prolactin levels and no clinically meaningful prolongation of the QT interval. At the same time, the antipsychotic efficacy of aripiprazole (15 mg/day to 30 mg/day) was similar to that of risperidone (Risperdal) (6 mg/day) or haloperidol (10 mg/day) in short-term clinical trials (Lieberman et al., 2002).
In a four-week, double-blind, randomized trial comparing two fixed-dose levels of aripiprazole (15 mg/day and 30 mg/day) with haloperidol (10 mg/day) and placebo in 414 patients with a primary diagnosis of schizophrenia or schizoaffective disorder, haloperidol and both doses of aripiprazole were found to be superior to placebo, and both medications appeared to have similar antipsychotic efficacy (Kane et al., 2002). Unlike haloperidol, however, neither dose of aripiprazole was associated with EPS or prolactin elevation. In the groups receiving haloperidol and 15 mg/day of aripiprazole, the percentage of patients showing a clinically significant weight gain (>7%) was significantly elevated (in comparison with placebo). Preliminary evidence suggests that weight gain is minimal over a 52-week period.
In December 2002, the FDA approved a new indication for clozapine: to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated in the International Suicide Prevention Trial (InterSePT), a two-year trial of 980 patients that compared clozapine to olanzapine. Clozapine treatment to reduce the risk of recurrent suicidal behavior should be continued for at least two years (Meltzer et al., 2003).
There is increasing evidence that clozapine also reduces the risk of recurrent aggressive behavior (Citrome et al., 2001; Volavka, 2002). It may also reduce alcohol and drug abuse problems among patients with schizophrenia (Drake et al., 2000), although the evidence for this is not based on controlled studies.
Differentiating the Products
All atypical antipsychotics have a lower propensity for EPS, and some of them perhaps have better efficacy for negative, cognitive and mood symptoms, compared to typical antipsychotics. What differentiates these products? Ease of use is an important consideration, with clozapine carrying a significant burden for white blood cell count monitoring. Having to titrate dose over time rather than starting at an efficacious dose is also an obstacle, and here clozapine, quetiapine (Seroquel), ziprasidone and risperidone are at a disadvantage compared to aripiprazole and olanzapine. Once-a-day dosing is also preferable, particularly to enhance compliance, and here the product labeling favors risperidone, olanzapine and aripiprazole over ziprasidone, quetiapine and clozapine. Having a short-acting IM formulation available for emergency use gives ziprasidone and soon olanzapine an important advantage in the management of patients in situations where oral administration is difficult. The availability of liquid or dissolvable preparations such as with risperidone and olanzapine can be an alternative to intramuscular injection for selected patients. New depot preparations (risperidone depot is expected to become available in the United States in 2003) will differentiate these products from the others for patients who have difficulty with adhering to their medication regimen over the long-term.
The side-effect profiles of the atypical antipsychotics also differ. Although all have less risk for EPS than the conventional agents, among the atypical antipsychotics, risperidone and ziprasidone can lead to EPS at higher doses that are still within the product labeling. Weight gain can be seen for clozapine, olanzapine, and, to a lesser extent, risperidone or quetiapine, but ziprasidone is considered essentially weight-neutral. Sustained elevations in serum prolactin can be seen with patients on risperidone but usually not with the other atypical antipsychotics. As with EPS, however, prolactin elevation may be seen at higher doses of the other atypical antipsychotics, as illustrated by a recent case report of a 17-year-old female on ziprasidone 180 mg/day (Jordan, 2003).
Finally, QTC prolongation is a concern for ziprasidone but not for the others.
Less certain are any differences in efficacy. This issue is complicated by the very nature of the disease, where treatment response may be quite different at the beginning of the illness compared with 20 years after onset. The availability of head-to-head, randomized, double-blind clinical trials studying different treatment domains will be illustrative.
To date, there is one published randomized, double-blind study comparing effects of clozapine, risperidone, olanzapine and haloperidol on psychotic symptoms (Volavka et al., 2002) and on cognition (Bilder et al., 2002). The latter study showed superiority of olanzapine and risperidone (but not of clozapine) over haloperidol in improving global cognitive functioning. Presentations at national meetings have suggested that quetiapine (Mueller et al., 2002), ziprasidone (Loebel et al., 2002) and aripiprazole (Cornblatt et al., 2002) may also benefit cognition.
Efficacy in reducing negative symptoms has been noted for all atypical antipsychotics, with some evidence published (Kane et al., 2002) or presented at meetings (Kujawa et al., 2002; Loebel et al., 2002). For treatment-resistant patients, clozapine appears to be relatively effective against negative symptoms (Volavka et al., 2002).
Optimal dosing is still being actively investigated, with very little information regarding dose response available for quetiapine, ziprasidone and aripiprazole, other than initial recommendations from the manufacturer based on premarketing registration studies.
Recent developments in antipsychotics show no major breakthroughs in terms of antipsychotic efficacy, but they do promise treatments that are safer, easier to administer and more acceptable to patients. Increasing variation among the available medications should enable a knowledgeable clinician to tailor psychopharmacological treatments to suit the individual patient's personal preference, response and side-effect history, and current medical condition. Novel mechanisms of action of some recent antipsychotics such as aripiprazole are heuristically interesting and may lead to better understanding of the pathophysiology underlying schizophrenia.
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