CLINICAL HANDBOOK OF SCHIZOPHRENIA

30 I. CORE SCIENCE AND BACKGROUND INFORMATIONsuaded psychiatric colleagues Hamon and Delay to use the drug on patients with psychoses.In subsequent years its use became widespread. Chlorpromazine represented the firstof a new class of so-called typical antipsychotic drugs. Subsequently, several other typicalantipsychotics were developed, with similar pharmacology and clinical effects.The history of atypical antipsychotics is almost as long. In 1958, Schmutz and colleaguessynthesized clozapine. Though effective as an antipsychotic, clozapine not onlyfailed to induce extrapyramidal symptoms in animal models but also showed the potentiallyfatal side effect of agranulocytosis. These factors initially slowed its adoptionworldwide. However, in 1989 a large study showed clozapine to have superior efficacyover the typical antipsychotics. Subsequently, a second generation of atypical antipsychoticswas developed. This class is now usually taken to include risperidone, olanzapine,quetiapine, and ziprasidone in addition to the older clozapine. Sertindole, aripiprazole,and amisulpride are sometimes included as well.The usefulness of the commonly used distinction between “typical” and “atypical”antipsychotics is controversial. In general, typical antipsychotics are usually described ashaving a common mechanism of D 2 blockade, effectiveness against positive symptoms, atendency toward extrapyramidal symptoms at high doses, a greater need for anticholinergicremedies to these symptoms, tardive dyskinesia with chronic use, and prolactinemia.Atypicals are usually described as having an effect on positive symptoms with fewerextrapyramidal side effects, a lesser need for anticholinergics, less prolactinemia, possibleimprovement in both negative and positive symptoms, and possible greater effectivenessin cases refractory to typical antipsychotics.Of note, a recent large trial found no reduction in extrapyramidal side effects in thenovel atypicals risperidone, olanzapine, ziprasidone, or quetiapine versus the typicalperphenazine. The distinction between “typical” and “atypical” antipsychotics may becomeless useful with the development of still newer agents whose properties do notclearly match either category.Typical AntipsychoticsTypical antipsychotics are proposed to act on positive symptoms by reducing activity inthe mesolimbic pathway, as discussed earlier. Unwanted side effects may occur via blockadeof the other pathways. Reductions in mesocortical activity may worsen cognitive andnegative symptoms. Nigrostriatal blockade may lead to Parkinsonian symptoms, andtuberoinfundibular blockade may lead to elevated prolactin and resultant galactorrhea,amenorrhea, and sexual dysfunction.The potency of typical antipsychotics correlates with their affinity for the D 2 receptor.In vivo PET studies show that therapeutic doses of most antipsychotics occupy 60–80% of D 2 receptors. Clinical response appears at a mean occupancy level of 65%.Hyperprolactinemia appears at a mean occupancy of 72%, and extrapyramidal symptomsappear at a mean occupancy of 78%. This also holds true for the majority of atypicalantipsychotics, with the exception of clozapine and quetiapine. These atypicalantipsychotics have clinical effects at merely 10–45% D 2 occupancy; the significance ofthis finding is discussed below.Recent computer models of D 2 receptor structure suggest that receptor binding is farmore complex than the “key-in-a-lock” description traditionally used. D 2 is a membraneboundreceptor whose structure contains seven helices spanning the membrane. Dopamineappears to bind in an epitope between helices 3, 4, 5, and 6, and acts by drawing togetherhelices 3 and 5. D 2 agonists appear to bind in the same epitope with similar effects.In contrast, D 2 antagonists divide into two classes. Class I agents (e.g., clozapine,