Historically, in vitro binding affinities of antipsychotics to D2 receptors have been used to predict efficacy, dose and possible side effects such as extrapyramidal symptoms (EPS) and endocrine disturbances . Positron emission tomography studies support this premise, indicating neuroleptic therapeutic efficacy and an increased risk of EPS at approximately 70% and 80% D2 receptor blockade, respectively . It has been speculated that the binding of 5-HT2A receptors may reduce the incidence of EPS by antagonizing the inhibitory control of serotonin on the dopaminergic system in the nigrostriatal pathway . The 5-HT2A-dopamine hypothesis of atypical antipsychotic action has become pronounced in the literature to the point that the ratio of 5-HT2A to D2 receptor blockade has been suggested to predict an agent’s potential for atypical antipsychotic properties . Whether the occurrence of EPS is the consequence of a reduced 5-HT2A to D2 ratio, or is dependent solely on increased D2 occupancy is still open for debate. birth control pills

Although D2 occupancy of clozapine may be higher than estimated, it is rapidly released or displaced from dopamine D2 receptors, resulting in apparent low D2 occupancy . As such, a rational augmenting agent selection, from a pharmacodynamic point of view, should be an agent that is more specific and shows tighter binding for dopamine D2 receptors. This premise was speculated to account for apparent enhanced clinical efficacy when sulpiride and risperidone were added to clozapine therapy in a randomized trial and an open trial, respectively. In addition, clozapine shows greater 5-HT2a receptor blockade relative to its D2 blockade at therapeutic doses, and it is desirable for any antipsychotic combination to retain this feature because it may offer protection against EPS.