CLINICAL HANDBOOK OF SCHIZOPHRENIA

3. Biological Theories 31raclopride) bind to the same epitope as dopamine, but prevents 3–5 coupling. Class IIagents (e.g., haloperidol, domperidone, spiperone, sulpiride) bind to an entirely differentepitope formed between the midsections of helices 2, 3, 6, and 7. Here, in addition to preventing3–5 coupling, they cause an entirely separate, strong coupling between helices 3and 6.These findings suggest that the process of D 2 antagonism may be more complex thansimple “blockade” of a receptor site. Some D 2 antagonists may work by binding to thesame site as dopamine, but without causing the necessary conformational changes for signaltransduction. Others may bind at an entirely different site, causing a conformationalchange that prevents dopamine from binding to its usual epitope.Atypical AntipsychoticsAtypical antipsychotics are generally considered to be effective against not only positivesymptoms but also negative symptoms, with a lower incidence of Parkinsonian side effectsand elevated prolactin. The most widely accepted model of how this occurs proposesthat atypical antipsychotics act via a dual blockade of not only D 2 but also serotonin5-HT 2A receptors. Serotonin inhibits dopamine release, but it does so to differentdegrees in different pathways. In the serotonin–dopamine antagonist hypothesis, 5-HT 2Ablockade reverses the effects of dopamine blockade in the nigrostriatal pathway, leadingto fewer Parkinsonian side effects. Similar reversals in the tuberoinfundibular andmesocortical pathways avoid the elevated prolactin and negative and cognitive side effectsseen with typical agents. However, serotonin’s inhibitory effect is considered minimalin the mesolimbic pathway. Hence, atypical agents still reduce mesolimbic activityand improve the symptoms of psychosis. In other words, adding 5-HT 2A blockade to D 2blockade is proposed to confine the effects of atypical agents to the desired (mesolimbic)pathway alone, thereby achieving the desired effects while avoiding the unwanted side effects.Objections have been raised to the 5-HT 2A –D 2 blockade theory of atypicality. First,there is no direct demonstration that adding 5-HT 2A antagonist agents to typicalantipsychotic regimen results in atypicality. Second, many typical antipsychotics have astrong component of 5-HT 2A blockade in addition to D 2 blockade. Third, some atypicalantipsychotics, such as risperidone, become ”typical” (i.e., give rise to extrapyramidalside effects) at higher doses despite near total 5-HT 2A blockade. Fourth, agents that block5-HT 2A without D 2 blockade are poorly effective as antipsychotics. Fifth, the degree ofatypicality among agents is considered to be quetiapine > olanzapine > risperidone,whereas the order of 5-HT 2A to D 2 blockade ratios for these agents is the opposite. Insummary, there are several lines of evidence that activity at 5-HT 2A is neither necessarynor sufficient to explain atypicality. The relevance of 5-HT 2A antagonism to atypicalityremains a subject of ongoing debate.An alternative account, known as the “fast-off” hypothesis, proposes that an agent’satypicality depends on its rate of dissociation from the D 2 receptor rather than its effectsat other receptors. In this model, all antipsychotics must block the D 2 receptor to be effectiveagainst positive symptoms. Their degree of atypicality depends on how easily theycan be displaced from the D 2 receptor by endogenous dopamine. In effect, they must be“strict” enough to block D 2 overactivity, but “permissive” enough to allow for somephysiological signaling.The fast-off proposal accommodates findings that clozapine and some other atypicalantipsychotics have significantly lower D 2 binding than typical agents. It also accommodatesthe observation that low D 2 affinity is a better predictor of atypicality than high 5-HT 2A