The atypical antipsychotic drugs have a more distinct pharmacological profile as opposed to the typical antipsychotics and they exert their action on a variety of receptors (Figure 6). Atypical antipsychotics generally have a high affinity for D2 receptors. However, some are also potent 5-HT2A receptor antagonists and have a variable selectivity for other receptors. The variation in the adverse effects within this drug class may be explained by this dissimilarity in the affinity and selectivity to various receptors.

Box 1 shows the atypical antipsychotics available and the affinity for the various receptors. Aripiprazole has a unique receptor profile in comparison to the other atypical antipsychotic drugs; it is a partial agonist at 5-HT1A and D2 receptors and an antagonist at 5-HT2A receptors.





























 

Clozapine


Individuals that are unresponsive or intolerant to antipsychotic therapy are considered to have treatment resistant schizophrenia (TRS). Studies have shown that the occurrence of TRS is between a fifth to a third of patients with schizophrenia. Clozapine is recommended for patients with TRS and is the only proven antipsychotic drug to be clinically effective. The use of clozapine is restricted for patients who have experienced an unsatisfactory improvement in the condition, despite the sequential use of a minimum of two different antipsychotic drugs (which includes an atypical antipsychotic), prescribed at an adequate dose and for a duration of four to six weeks.

The use of clozapine is limited due to the risk of serious agranulocytosis and neutropenia it possesses. These risks have been minimised through the use of an approved clozapine monitoring service, which is compulsory for patients that are being treated with clozapine in the UK. The specific monitoring requirements are set out in the clozapine product information.

The exact mechanism for the action of clozapine remains unknown. Studies have shown that at therapeutic doses, clozapine has 20-67% occupancy at D2 receptors in the striatum as opposed to typical antipsychotics that have approximately 70-89% occupancy. This may explain the relatively low incidence of EPS associated with clozapine at a therapeutic dose and therefore the effectiveness for those individuals that experience tardive dyskinesia with other antipsychotic's. Clozapine also exerts its action on histamine H1, alpha-1 and muscarinic (m1-5) receptors.