Aripiprazole(Drug information on aripiprazole) acts as a partial D2 and 5-HT1A agonist. Presumably, it acts like a D2 antagonist when dopamine(Drug information on dopamine)rgic 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(Drug information on risperidone) (Risperdal) (6 mg/day) or haloperidol(Drug information on 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.Clozapine
In December 2002, the FDA approved a new indication for clozapine(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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.