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TABLE 371-14
profile makes it most appropriate for treatment- resistant cases. Risperidone, a benzisoxazole derivative, is more potent at 5HT than D re- ceptor sites, like clozapine, but it also exertssignificant ␣ antagonism, a property that may contribute to its perceived ability to improve mood and increase motor activity. Risperidone is not as effective as clozapine in treatment- resistant cases but does not carry a risk of blood dyscrasias. Olanzapine is similar neurochemi- cally to clozapine but has a significant risk of inducing weight gain. Quetiapine is distinct in having a weak D effect but potent ␣ and his- tamine blockade. Ziprasidone causes minimal weight gain and is unlikely to increase prolac- tin, but may increase QT prolongation. Aripi- prazole also has little risk of weight gain or prolactin increase but may increase anxiety, nausea, and insomnia as a result of its partial Conventional antipsychotic agents are ef- fective in 70% of patients presenting with a first episode. Improvement may be observed within hours or days, but full remission usually requires 6 to 8 weeks. The choice of agent de-pends principally on the side-effect profile and cost of treatment or on a past personal or family history of a favorable response to the drug in question. Atypical agents appear to be more effective in treating negative symptoms and improving cognitive function. An equivalent treatment response can usually be achieved with relatively low doses of any drug selected, i.e., 4 to 6 mg/d of haloperidol, 10 to 15 mg of olanzapine, or 4 to 6 mg/d of risperidone.
blockade, and there is little evidence that higher doses increase either the rapidity or de- gree of response. Maintenance treatment re-quires careful attention to the possibility of re- Note: EPSEs, extrapyramidal side effects; WBC, white blood count.
lapse and monitoring for the development of amovement disorder. Intermittent drug treat- etiology. The mechanism of action involves, at least in part, blockade ment is less effective than regular dosing, but gradual dose reduction of dopamine receptors in the limbic system and basal ganglia; the is likely to improve social functioning in many schizophrenic patients clinical potencies of traditional antipsychotic drugs parallel their affin- who have been maintained at high doses. If medications are completely ities for the D receptor, and even the newer “atypical” agents exert discontinued, however, the relapse rate is 60% within 6 months. Long- some degree of D receptor blockade. All neuroleptics induce expres- acting injectable preparations are considered when noncompliance sion of the immediate-early gene c-fos in the nucleus accumbens, a with oral therapy leads to relapses. In treatment-resistant patients, a dopaminergic site connecting prefrontal and limbic cortices. The clin- transition to clozapine usually results in rapid improvement, but a pro- ical efficacy of newer atypical neuroleptics, however, may involve D , longed delay in response in some cases necessitates a 6- to 9-month D , and D receptor blockade, ␣ - and ␣ -noradrenergic activity, and/ or altering the relationship between 5HT and D receptor activity, as Antipsychotic medications can cause a broad range of side effects, well as faster dissociation of D binding.
including lethargy, weight gain, postural hypotension, constipation, Conventional neuroleptics differ in their potency and side-effect and dry mouth. Extrapyramidal symptoms such as dystonia, akathisia, profile. Older agents, such as chlorpromazine and thioridazine, are and akinesia are also frequent with traditional agents and may con- more sedating and anticholinergic and more likely to cause orthostatic tribute to poor compliance if not specifically addressed. Anticholin- hypotension, while higher potency antipsychotics, such as haloperidol, ergic and parkinsonian symptoms respond well to trihexyphenidyl, 2 perphenazine, and thiothixene, are more likely to induce extrapyra- mg bid, or benztropine mesylate, 1 to 2 mg bid. Akathisia may respond midal side effects. The model atypical antipsychotic agent is clozapine, to beta blockers. In rare cases, more serious and occasionally life- a dibenzodiazepine that has a greater potency in blocking the 5HT threatening side effects may emerge, including ventricular arrhyth- than the D receptor and a much higher affinity for the D than the D mias, gastrointestinal obstruction, retinal pigmentation, obstructive receptor. Its principal disadvantage is a risk of blood dyscrasias. Unlike jaundice, and neuroleptic malignant syndrome (characterized by hy- other antipsychotics, clozapine does not cause a rise in prolactin level.
perthermia, autonomic dysfunction, muscular rigidity, and elevated Approximately 30% of patients have a better response to these agents creatine phosphokinase levels). The most serious adverse effects of than to traditional neuroleptics, suggesting that they will increasingly clozapine are agranulocytosis, which has an incidence of 1%, and in- displace the older-generation drugs. Clozapine appears to be the most duction of seizures, which has an incidence of 10%. Weekly white effective member of this class and has demonstrated superiority to blood cell counts are required, particularly during the first 3 months other atypical agents in preventing suicide; however, its side-effect


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