[Third-generation antipsychotics: focus on cariprazine]

Antipsychotic drugs represent a fundamental aid for the treatment of schizophrenia and other psychiatric disorders. However, the definition of antipsychotics includes molecules that are extremely heterogeneous when considering their mechanism of action and the clinical implications. While in the first part of this review the major critical issues in the treatment of schizophrenia will be highlighted, the attention will then focus on the major pharmacological 'innovation' in recent years, which is represented by the development of partial agonists for the D2 and D3 receptors, a strategy that may guarantee a 'stabilization' of impaired dopaminergic function in the schizophrenic patient. One such drug is cariprazine that differs from other molecules due to its greater affinity for the dopaminergic D3 receptor. Next, it will be described receptor and functional mechanisms that characterize the action of cariprazine, both with respect to other partial agonists as well as with respect to second-generation antipsychotics. More specifically, it will be highlighted the peculiarities of cariprazine and how these mechanisms could modify the functionality of specific brain circuits associated with major functional domains that are altered in schizophrenia. The activity of partial agonist at dopaminergic D3 receptors, which is dominant as compared to other receptor mechanisms, represents the mechanism that is most likely associated with the improvement of negative symptoms and of specific components such as motivational deficits. Furthermore, this mechanism together with the binding to other receptors is also compatible with a positive effect on cognitive deficits, often associated with reduced functionality of the prefrontal cortex, as well as in the substance abuse, a relevant problem of co-morbidity with schizophrenia.