The newer, second generation of “atypical” nonphenothiazine antipsychosis drugs that have complex effects on the dopamine and serotonin systems are now used in preference to the standard dopamine antagonists, the phenothiazines and the butyrophenones. They are “atypical” in that their extrapyramidal side effects are far less than that for the phenothiazines. They all serve to calm the patient, blunt emotional responses, and reduce hallucinosis and aggressive and impulsive behavior, leaving cognitive functions relatively intact. The main side effects, pertaining mostly to the phenothiazine group, are summarized in Table 49-1 and in Chap. 41 (see also the review by Freedman and the chapter by Baldessarini). The antipsychotic action of these drugs is more impressive in the short and intermediate term than over the long term, although some data suggest that they are also of value in preventing relapses. Negative symptoms (apathy and withdrawal) respond less well than positive ones, and it is generally acknowledged that 10 to 20 percent of patients respond little or not at all to medication.
Clozapine, olanzapine, risperidone, quetiapine, and others listed in Table 49-2 are the more recently introduced atypical drugs with incompletely defined pharmacologic properties but with narrower affinities for certain receptors. In addition to their reduced motor side effects, they produce clinical improvement in about half of patients who have proved to be unresponsive to other antipsychotic medications. These drugs bind to and inhibit serotonin receptors and, to some extent, dopamine receptors (Meltzer and Nash), but have a much lower affinity for striatal dopamine receptors, thus providing a major advantage—the absence of immediate or tardive extrapyramidal side effects. This has led most psychiatrists to use one of the newer drugs, rather than the phenothiazines, as a first choice. The addition of a second drug, specifically combining clozapine with risperidone, was not found to be useful in the trial conducted by Honer and colleagues. Moreover, in another one of the effectiveness trials sponsored by the National Institutes of Mental Health, Lieberman and colleagues (“CATIE” Investigators) found that the majority of chronic schizophrenics discontinued their antipsychosis drugs within 18 months. Among the medications they compared, olanzapine was slightly more effective than quetiapine, risperidone, and ziprasidone; of equal interest, the phenothiazine perphenazine was equivalent in efficacy and tolerability to the last 3 second-generation (atypical) drugs. Approximately 1 percent of patients treated with one of the most effective drugs, clozapine, develop leukopenia, which may prove fatal; there is less risk with the related agent, olanzapine, but leukopenia and agranulocytosis have been reported in rare instances with it as well. Orthostatic hypotension, tachycardia, fever, and hypersalivation may be troublesome in the first days and weeks of therapy with any agent in this class. Risperidone is a potent serotonin and dopamine receptor antagonist. Low doses reportedly attenuate the negative symptoms of schizophrenia (apathy, emotional withdrawal, lack of social interaction) and the incidence of extrapyramidal side effects is low provided that the dosage is kept below 6 mg daily.