The question then becomes, ‘what constitutes an appropriate augmenting antipsychotic’? With limited literature focusing on antipsychotic polypharmacy, the best approach to this query involves a rational application of pharmacodynamic and pharmacokinetic principles. Because each antipsychotic displays a unique pharmacodynamic and pharmacokinetic profile, it is necessary to consider the contributions of each agent when two antipsychotics are combined. In the present paper, augmentation of the atypical antipsychotic clozapine with a second antipsychotic is presented as an example and is based on the approach proposed above.


In contrast to the majority of conventional antipsychotics and risperidone, clozapine has extensive diversity in its receptor binding profile while having reduced affinity for dopamine (D)2 receptors. This property, linked to its increased therapeutic efficacy, has led to an explosion in research focused on the elucidation of atypical mechanisms of neuroleptic action. However, the dopamine hypothesis of schizophrenia, which postulates that blockade of mesolimbic D2 receptors is responsible for the therapeutic action, continues to provide an evidence-based explanation for conventional antipsychotic efficacy. buy ampicillin

The criteria for rational selection of an augmenting antipsychotic can be separated into the following three major features: 5-hydroxytryptamine (HT)2a/D2 receptor antagonism, complementary effects of antipsychotic blockade of other receptor sites (notably the alpha1-adrenergic, muscarinic cholinergic, and histaminic receptor sites), and pharmacokinetic considerations including cytochrome P450 metabolism.